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There are some conflicting etymologies for the origin of the name, with some claiming it was named after a cacique of the region whose name was Guayrá or Guayracá. Alternatively, the word might come from Guarani "kwa y ra" ("can not pass", "impassable") or even "guay ra" ("river that goes [beyond]").
The limits of Guayrá were the Iguazu River on the south, the Paraná River on the west, the Tiete (or Añemby) River to the north, and the line of the Treaty of Tordesillas to the east. The Tiete also marked the boundary between the Tupi and Guarani Indians.
The town of Ontiveros was founded by Captain Garcia Rodriguez de Vergara on orders from Domingo Martínez de Irala in 1554. It was located on the left bank of the Paraná, between the Iguazu and Pipiri-Guazu, about 50 kilometres (31 miles) north of Salto del Guairá, in the territory of the cacique Canendiyu. It was intended to serve as a connection to Portuguese Colonial Brazil.
Ciudad Real del Guayrá, also referred to as Guayrá and the present day Guaíra, Paraná, was founded by Captain Ruy Diaz Melgarejo in 1556. It is on the left bank of the Paraná at the confluence of the Pipiry-Guazu.
Guayrá was covered with dense forest and many rivers, and by 1600, it had become a place of refuge for the Guarani from the encomenderos of Paraguay and the esclavistas of Brazil.
It was the main region occupied by the Spanish Jesuit reductions of the indigenous peoples, at the Jesuit Missions of the Guaranis. However, it was destroyed by the bandeirantes from São Paulo in 1631.