De Soto's body was sunk in the Mississippi, and his widow governed Cuba and fought his business partner over the estate until 1546 to 1550

Hernando de Soto returned from Peru in 1536 with about 18,000 ounces of gold. Charles V made him Adelantado of Florida and Governor of Cuba. The Crown also promised him the title of marquis over a part of the land he conquered, with de Soto to choose the part. He married Isabel de Bobadilla, daughter of Pedrarias Dávila, in Valladolid in November 1536. They had no children. On 13 May 1539 in Havana he made a will. It left 400 ducats to "a boy they say is my son," Andrés de Soto, and 1,000 ducats to his daughter María in Nicaragua. A power of attorney put Isabel over all his property, Indians and slaves. He sailed for Florida on 17 May and left Isabel governing Cuba. Within days his partner from Peru, Hernán Ponce de León, said he had been forced to give de Soto 10,000 pesos of gold and demanded it back from Isabel. De Soto died of fever at Guachoya in 1542. His men buried him at night. When local people noticed the fresh earth, the men dug up the body, weighted it, and dropped it into the Mississippi from a canoe. Isabel received confirmation of his death on 4 December 1543. The expedition's losses ruined her, and most of the will's bequests were never paid. The lawsuit with Ponce de León, Archivo General de Indias, Justicia 750, runs to more than 2,000 folios and ended between 1546 and 1550. The marquisate was never granted. The last record of Isabel is in Seville in 1546.