The Italian city of Venice was one of the largest cities in medieval and Renaissance era Europe. It was the center of the Republic of Venice, a maritime empire in the Mediterranean, and had one of Europe's largest ports for exotic goods (particularly from Asia), or luxury goods such as glassware. Impact of plague While its population was relatively small by modern standards, it is believed that Venice was among the five most populous cities in Western Europe in the given years between 1050 and 1650. The city's population did fluctuate over time due to devastating pandemics, and it is believed that Venice was one of the main points of entry for the Black Death in Europe. Venice was one of the hardest-hit cities during the Black Death; estimates fluctuate greatly across sources, but it is believed that the city lost around 40 percent of its population during the initial outbreak in the 1340s. Decline Furthermore, Venice lost roughly a third of its population during further plague pandemics (both introduced via war) in the 1570s and 1630s. Because of this, the population was kept fairly consistent across the given years between 1600 and 1800. The 18th century also saw the decline of the Venetian Empire, as other states gained power and influence in the Mediterranean. Venice also lost its importance as the entry point of exotic goods into Europe, as other European powers had already established their own maritime empires and trade routes across the globe. Eventually, the crumbling Venetian Empire fell to Napoleon in 1796, and its overseas territories were gradually taken by or split among various other powers. While the empire fell, the city itself continued to be a center for art and culture in Europe, and it has maintained this status until today. In 2021, Venice had a population of more than 250,000 people.

During the Medieval period, the Italian state of Venice grew into one of the most powerful empires in the Mediterranean. Its merchants, most famously Marco Polo, were some of the most important importers of exotic goods into Europe via their trade connections through the Black Sea and along the Silk Road. The city itself was among the most populous in Europe from the 12th to 16th centuries, its territories in the Italian mainland (terraferma) grew in the early 1400s, as well as its control over much of the Adriatic coast in the Balkans. By the mid-16th century, the population of the Venetian Republic was roughly 2.3 million people, at a time when Europe's population was around 70 million. 1.7 million of this population was concentrated in northeast Italy, while the islands of Crete and Cyprus were the most populous overseas territories.

In 1500, the largest city was Paris, with an estimated 225 thousand inhabitants, almost double the population of the second-largest city, Naples. As in 1330, Venice and Milan remain the third and fourth largest cities in Western Europe, however Genoa's population almost halved from 1330 until 1500, as it was struck heavily by the bubonic plague in the mid-1300s. In lists prior to this, the largest cities were generally in Spain and Italy, however, as time progressed, the largest populations could be found more often in Italy and France. The year 1500 is around the beginning of what we now consider modern history, a time that saw the birth of many European empires and inter-continental globalization.

Throughout the early modern period, the largest city in Italy was Naples. The middle ages saw many metropolitan areas along the Mediterranean grow to become the largest in Europe, as they developed into meeting ports for merchants travelling between the three continents. Italy, throughout this time, was not a unified country, but rather a collection of smaller states that had many cultural similarities, and political control of these cities regularly shifted over the given period. Across this time, the population of each city generally grew between each century, but a series of plague outbreaks in the 1600s devastated the populations of Italy's metropolitan areas, which can be observed here. Naples At the beginning of the 1500s, the Kingdom of Naples was taken under the control of the Spanish crown, where its capital grew to become the largest city in the newly-expanding Spanish Empire. Prosperity then grew in the 16th and 17th centuries, before the city's international importance declined in the 18th century. There is also a noticeable dip in Naples' population size between 1600 and 1700, due to an outbreak of plague in 1656 that almost halved the population. Today, Naples is just the third largest city in Italy, behind Rome and Milan. Rome Over 2,000 years ago, Rome became the first city in the world to have a population of more than one million people, and in 2021, it was Italy's largest city with a population of 2.8 million; however it did go through a period of great decline in the middle ages. After the Fall of the Western Roman Empire in 476CE, Rome's population dropped rapidly, below 100,000 inhabitants in 500CE. 1,000 years later, Rome was an important city in Europe as it was the seat of the Catholic Church, and it had a powerful banking sector, but its population was just 55,000 people as it did not have the same appeal for merchants or migrants held by the other port cities. A series of reforms by the Papacy in the late-1500s then saw significant improvements to infrastructure, housing, and sanitation, and living standards rose greatly. Over the following centuries, the Papacy consolidated its power in the center of the Italian peninsula, which brought stability to the region, and the city of Rome became a cultural center. Across this period, Rome's population grew almost three times larger, which was the highest level of growth of these cities.