Cigarette smoking is a leading cause of many adverse health consequences. Chronic nicotine exposure leads to insulin resistance, and may increase the risk of developing non-insulin-dependent diabetes mellitus (NIDDM) in young otherwise healthy smokers. To evaluate smoking-induced effects on carbohydate metabolism, we studied muscle glycogen recovery from exercise in a young healthy population of smokers. The study used ³¹P/¹³C nuclear magnetic resonance (NMR) spectroscopy to compare muscle glycogen and glucose-6-phosphate levels during recovery in exercised gastrocnemius muscles of randomized cohorts of healthy male smokers [S] and controls [C]. Data for the two groups were: smokers [S] (20 cigarettes/day, n=8, 24±2y, 173±3cm, 70±4kg) and age/weight matched non-smoking controls [C] (n=10, 23±1y, 175±3cm, 67±3kg). Subjects performed single-leg toe-raises to deplete glycogen to ~20mmol/l, and glycogen re-synthesis was measured during the first 4hrs of recovery. Plasma samples were assayed for glucose and insulin at rest and during recovery. Test subjects were recruited from the general community surrounding Yale University. Glycogen was depleted to similar levels in the two groups (23.5±1.2mmol/l, S and 19.1±1.3mmol.l, C). During the first hour of recovery glycogen synthesis rates were similar (13.8±1.1mmol/l-hr, S and 15.3±1.3 mmol/l-hr, C). Between hours 1 and 4 glycogen synthesis was impaired in smokers (0.8±0.2 mmol/l-hr, S and 4.5±0.5 mmol/l-hr, C, p=0.0002) compared with controls. Glucose-6-phosphate was reduced in smokers during hours 1-4 (0.105±0.006mmol/l, S and 0.217±0.019 mmol/l, C, p=0.0212). We conclude that cigarette smoking impairs the insulin dependent portion of muscle recovery from glycogen depleting exercise. This impairment likely results from a reduction in glucose uptake.