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The Santarém region has been a center of human settlement for many thousands of years. In 1661, more than 20 years after Pedro Teixeira’s expedition first contacted the local Tupaiu Indians, a Jesuit mission was established at the meeting of the Tapajós and Amazonas, and officially named Santarém in 1758.

The later history of Santarém was marked by the rubber boom and bust, and a series of gold rushes that started in the 1950s. The economy today is based on rubber, soy and hardwoods, plus Brazil nuts, black pepper, mangoes, jute and fish. The discovery of gold and bauxite and the construction of the Curuá-Una hydroelectric dam, 60km southeast of Santarém, have brought some development in the last 25 years, but it is still largely isolated. A movement to form a new state of Tapajós has some popular support here, but little traction outside the region.