Updated project metadata. Visceral adiposity is a risk factor for severe COVID-19, and a link between adipose tissue infection and disease progression has been proposed. Here we demonstrate that SARS-CoV-2 infects human adipose tissue and undergoes productive infection in human primary adipose-derived stromal-vascular cells differentiated into adipocytes. However, the permissiveness to infection and the cellular response depends on the anatomical origin of the cells and the viral lineage. Cells of visceral adipose tissue origin express more ACE2 and are more permissive to SARS-CoV-2 infection than their subcutaneous counterpart. SARS-CoV-2 infection leads to inhibition of lipolysis in cells of subcutaneous origin, while in visceral fat cells, it results in higher expression of pro-inflammatory cytokines. Viral load and cellular response are attenuated when visceral adipose tissue cells are infected with the SARS-CoV-2 gamma variant. A similar degree of cell death occurs 4-days after SARS-CoV-2 infection, regardless of the cell origin or viral lineage. Hence, SARS-CoV-2 infects human adipose tissue cells, replicating and altering cell function and viability in a fat depot- and viral lineage-dependent fashion.