After the death of his first benefactor Lorenzo de Medici in 1492, Michelangelo lived for a year with a community of Augustine monks associated with the famous basilica, studying anatomy in the hospital they ran.
As a thank you for their welcome, he left them a 1.40 metre (four and a half foot) sculpture of a nude Jesus Christ on the cross.
The masterpiece was thought lost for decades before it was found in the 1960s, in a convent corridor and so badly overpainted it was barely recognisable.
Now restored, it recently went on tour in Italy before returning Tuesday to take up a new setting in Santo Spirito: suspended above the church's old sacristry in a way that allows visitors to inspect it from all angles.
"The Santo Spirito district, with its extraordinary basilica, is a place that needs protecting and to be brought to life," said Simonetta Brandolini d'Adda, president of the Friends of Florence group which helped organise the new installation for "this serene, sublime Christ."