The mitochondrial dysfunction characteristic of heart failure (HF) is associated with changes in intracellular nicotinamide adenine dinucleotide (NAD⁺) and NADH levels. Raising NAD⁺ levels with the NAD⁺ precursor, nicotinamide riboside (NR), may represent a novel HF treatment. In this 30-participant trial of patients with clinically stable HF with reduced ejection fraction, NR, at a dose of 1,000 mg twice daily, appeared to be safe and well tolerated, and approximately doubled whole blood NAD⁺ levels. Intraindividual NAD⁺ increases in response to NR correlated with increases in peripheral blood mononuclear cell basal (R² = 0.413, P = 0.003) and maximal (R² = 0.434, P = 0.002) respiration, and with decreased NLRP3 expression (R² = 0.330, P = 0.020). (Nicotinamide Riboside in Systolic Heart Failure; NCT03423342)