Extrapulmonary manifestations of COVID-19 have gained attention, not only due to their links to clinical outcomes, but also due to their potential long-term sequelae. Recent evidence has shown multi-organ tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including heart, kidney and liver. Previous studies have shown that close to 20% of hospitalized patients with COVID-19 develop liver injury, showing an association to disease severity. Here, we characterized SARS-CoV-2 liver tropism in autopsy samples, based on the expression of cell-entry facilitators in parenchymal cells, clinical polymerase chain reaction (PCR) positivity, subgenomic SARS-CoV-2 identification using RNA sequencing, and viral RNA detection by in situ hybridization. Next, we unraveled the transcriptomic  landscape of SARS-CoV-2 liver tropism, revealing significant increases in interferon alpha and gamma signaling and compensatory liver-specific metabolic regulation. While these results reflect changes in tissues from patients with severe SARS-CoV-2 infection, the profound molecular alterations raise questions about the potential long-term consequences of COVID-19 infection.