Ruy Díaz Ortiz Melgarejo was born in Salteras of Seville, in the southermost region of Andalusia.

[2] Melgarejo escaped from jail, but was captured by Tupi Indians who killed and ate his traveling companion.

[2] In 1555, Melgarejo returned to Asunción, where he was welcomed by the current governor, Domingo Martínez de Irala.

[3] Elvira was the sister-in-law of Juan de Garay and a descendant of powerful dynasties of the former medieval kingdoms of Castile and Leon, the houses of Mendoza and Guzman.

The name, translated as "rich town", was selected due to Melgarejo's belief that there were silver mines nearby.

[2] Melgarejo was the leader of an expedition to Ontiveros, then capital of the region, a city founded three years earlier by another Irala lieutenant.

[5] He instead created a new settlement, Ciudad Real, on higher ground across the Paraná River from the original Ontiveros site.

Bad weather early in the voyage forced them to stop at the port of San Vicente in Brazil, where Melgarejo was commissioned to assist the Governor in battles against natives.