A complex interplay exists between plasma lipoproteins and inflammation, as evidenced from studies on atherosclerosis. Alterations in plasma lipoprotein levels in the context of infectious diseases, particularly respiratory viral infections, such as SARS-CoV-2, have become of great interest in recent years, due to their potential utility as prognostic markers. Patients with severe COVID-19 have been reported to have low levels of total cholesterol, HDL-cholesterol, and LDL-cholesterol, but elevated levels of triglycerides. However, detailed characterization of particle number and size of the different plasma lipoproteins in patients with COVID-19 has yet to be reported. In this pilot investigational study, NMR spectroscopy was used to characterize lipoprotein particle numbers and sizes, as well as various metabolites, in 32 patients with severe COVID-19 admitted to the intensive care unit. Our study revealed markedly reduced HDL particle (HDL-P) numbers at presentation, with especially low numbers of small-sized HDL-P (S-HDL-P), along with elevated triglyceride-rich lipoprotein particle numbers (TRL-P), particularly the very small- and small-sized TRL subfractions. Moreover, patients with severe COVID-19 were found to have remarkably elevated GlycA levels, as well as elevated levels of branched-chain amino acids and beta-hydroxybutyrate. Finally, we detected elevated levels of lipoproteins X and Z in most participants, which are distinct markers of hepatic dysfunction and therefore, novel findings of this study.