Background/Objectives: Hexosylceramides (HexCers) are bioactive lipids whose circulating levels have been associated with severe illness. Blood lipid profiles differ between COVID-19 and non-COVID-19 sepsis and are also affected by liver cirrhosis. To evaluate the impact of SARS-CoV-2 infection and investigate associations with disease severity and underlying liver cirrhosis among circulating HexCer species, we analyzed plasma samples from patients with systemic inflammatory response syndrome (SIRS), sepsis, or septic shock. Methods: Plasma levels of five HexCer species were quantified by flow injection analysis tandem mass spectrometry (FIA-MS/MS) in 159 patients with SIRS, sepsis, or septic shock. Among these patients, 24 had COVID-19, and 31 liver cirrhosis. In addition, serum HexCer levels were analyzed in 41 patients with moderate and 61 patients with severe COVID-19. Results: Patients with SIRS, sepsis or septic shock exhibited largely comparable plasma HexCer18:1;O2/22:0, 23:0, and 24:0 concentrations, all of which were significantly lower than those observed in healthy controls. These species and in addition HexCer18:1;O2/16:0 and 24:1 levels were modestly lower in patients with septic shock compared to those with SIRS. No significant differences in any of the five HexCer species were observed between patients with COVID-19 and non-COVID-19 septic shock or between ventilated patients with and without COVID-19, indicating that circulating HexCer levels are associated with disease severity rather than SARS-CoV-2 infection. HexCer18:1;O2/24:1 levels were increased in patients with cirrhosis. No significant differences in HexCer levels were observed between survivors and non-survivors. Conclusions: In COVID-19 and non-COVID-19 patients circulating levels of HexCer18:1;O2/22:0, HexCer18:1;O2/23:0, and HexCer18:1;O2/24:0 decline early during systemic inflammation, whereas reductions in HexCer18:1;O2/16:0 and 24:1 levels become apparent in septic shock. These findings indicate that alterations in circulating HexCer species reflect sepsis severity rather than being specific to COVID-19.