The levels of the essential pyridine nucleotide, NAD+ and its reduced form NADH have not been documented in MS patients. We aimed to investigate NAD+ and NADH levels in serum in patients with different disease stages and forms of MS. NAD+ and NADH levels were measured in the serum from 209 patients with relapsing remitting MS (RRMS), 136 with secondary progressive MS (SPMS), 51 with primary progressive MS (PPMS), and 99 healthy controls. All patients were in a clinically stable phase. Serum NAD + levels declined by at least 50% in patients with MS compared to controls (17.9±3.2 μg/ml; p=0.0012). Within the MS sub-groups NAD + levels were higher in RRMS (9.9±2.9 μg/ml; p=0.001) compared to PPMS (6.3±2.1 μg/ml; p=0.003) and SPMS (7.8±2.0 μg/ml; p=0.005). A two-fold increase in NADH levels (p=0.002) and at least three-fold reduction in the NAD+/NADH ratio (p=0.009) were observed in MS patients compared to controls. Serum NAD+ and NADH levels are may be associated with disease progression in MS. Given the importance of NAD+ in the maintenance of normal cellular function, it is likely that this molecule is of therapeutic relevance in MS.