The palace was built between 1530 and 1540 for the Grimaldi family and became later in the hands of the Brignole Sale family. In 1899, the Duchess of Galliera, Maria Brignole Sale and last member of the family bequeathed the palace to the city of Genoa.

Palazzo Bianco is part of the UNESCO WORLD HERITAGE SITE, the Strada Nuova, including three Strada Nuova Museums, the Palazzo Rossi, the Palazzo Bianco, the Palazzo Doria Tursi, and the palaces Palazzo Spinola National Gallery and the Royal Palace Museum.

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