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Nicotinamide adenine dinucleotide (NAD+) depletion has been postulated as a contributor to the severity of COVID‐19; however, no study has prospectively characterized NAD+ and its metabolites in relation to disease severity in patients with COVID‐19. We measured NAD+ and its metabolites in 56 hospitalized patients with COVID‐19 and in two control groups without COVID‐19: (1) 31 age‐ and sex‐matched adults with comorbidities, and (2) 30 adults without comorbidities. Blood NAD+ concentrations in COVID‐19 group were only slightly lower than in the control groups (p < 0.05); however, plasma 1‐methylnicotinamide concentrations were significantly higher in patients with COVID‐19 (439.7 ng/mL, 95% CI: 234.0, 645.4 ng/mL) than in age‐ and sex‐matched controls (44.5 ng/mL, 95% CI: 15.6, 73.4) and in healthy controls (18.1 ng/mL, 95% CI 15.4, 20.8; p < 0.001 for each comparison). Plasma nicotinamide concentrations were also higher in COVID‐19 group and in controls with comorbidities than in healthy control group. Plasma concentrations of 2‐methyl‐2‐pyridone‐5‐carboxamide (2‐PY), but not NAD+, were significantly associated with increased risk of death (HR = 3.65; 95% CI 1.09, 12.2; p = 0.036) and escalation in level of care (HR = 2.90, 95% CI 1.01, 8.38, p = 0.049). RNAseq and RTqPCR analyses of PBMC mRNA found upregulation of multiple genes involved in NAD+ synthesis as well as degradation, and dysregulation of NAD+‐dependent processes including immune response, DNA repair, metabolism, apoptosis/autophagy, redox reactions, and mitochondrial function. Blood NAD+ concentrations are modestly reduced in COVID‐19; however, NAD+ turnover is substantially increased with upregulation of genes involved in both NAD+ biosynthesis and degradation, supporting the rationale for NAD+ augmentation to attenuate disease severity. [ABSTRACT FROM AUTHOR]