Columbus originally reached the Chinese port of Fuzhou on his second voyage. However he had nothing with which to trade and after preliminary talks with the city officials, he returned to Spain to relay the news of his discoveries. The Spanish commissioned a textiles mission to Fuzhou in 1498, though this too met with little success when it tried to trade with the Chinese market. A religious mission was also arranged in 1499, and landed at Ningbo in August.

By 1500 the Portuguese also established trade relations with China, with Vasco Da Gama arriving at Ningbo and buying up some gunpowder and supplies for silver. However upon leaving the port, his fleet seized to merchant vessels just outside the harbour, and fled on before they were apprehended.

1501 saw Juan Ponce de Leon explore the Yellow sea and Bay of Bohai in April, trading what he could in Qingdao and Incheon.

1502 Jorge Alvares, sailing for the Portuguese crown, arrived in Guangzhou. Later that year the Spanish reached Beijing, with Juan Urraca Coruna leading an embassy with tribute to the court of Hongzhi. The emperor was very interested in the lands to the east, and accommodated the embassy for a few months. However news of the Portuguese attack upon the Sultanate of Malacca, strained relations between the emperor and his european guests, and the mission left soon after.

From 1504-1508 there were a few counts of piracy by both Spanish and Portuguese sailors on journeys to the Indies. Relations became ever more fraught, even as another five ambassadorial missions were organised, three Spanish missions in 1504, 1512 and 1519 and two by Portugal in 1506 and 1511.The 1510s saw an increase of trade between Europe and China, and with it came more counts of piracy and other crimes.

The two European powers were not always amicable with one another either, Spanish traders arresting and killing Portuguese explorers in Shanghai in 1512. After an attack by the Portuguese on their colony in Sri Lanka in 1516, the Spanish even encouraged the Chinese court to expel Portuguese traders.

In 1520 there was a Chinese decree limiting European trade in China to Zhoushan Island by Ningbo harbour. Later in 1524 this was changed, making the Portuguese trade via Macau in Guangzhou harbour.

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