Statins are commonly prescribed to avert cardiovascular disease in diabetics. Little information, however, exists about the interrelationship of obesity, fitness, and statin treatment on mortality.Our objective was to evaluate the influence of statin therapy on body mass index (BMI), cardiorespiratory fitness, and all-cause mortality risk in diabetics.We gathered prospective observational data from Veterans Affairs Medical Centers in Washington, DC, and Palo Alto, California, on type 2 diabetic male veterans (n = 3775; mean age = 58.9 ± 9.9 years) who underwent an exercise tolerance test during the period of 1986 to 2011.There were 930 deaths during a mean follow-up period of 10.5 years (37 826 person-years), with an average annual mortality of 24.6 events per 1000 person-years of observation. Adjusted Cox proportional hazard analysis revealed that mortality risk was 34% lower (hazard ratio [HR] = 0.66; confidence interval [CI] = 0.57-0.77) for individuals treated with statins compared with those not on statins. There was a paradoxical BMI-mortality association, with the highest mortality in those with a BMI of 18.5 to 24.9 kg/m(2) (HR = 1.54; CI = 1.26-1.87, P < .0001) compared with obese subjects (BMI of 30-34.9 kg/m(2)). However, this paradoxical association was evident only in those not treated with statins (HR = 1.79; CI = 1.39-2.29; P < .001) vs those on statins (HR = 1.06; CI = 0.75-1.54; P = .70). When statin therapy and fitness status were combined, mortality risk was 44% higher (HR = 1.44; CI = 1.16-1.78) in the least-fit not treated with statins compared with the least-fit treated with statins. Mortality risk declined progressively with increased fitness to 60% lower (HR = 0.40; CI = 0.24-0.66) and 49% lower (HR = 0.51; CI = 0.38-0.68) for the most highly fit individuals (>9 metabolic equivalents) treated and not treated with statins, respectively.Statin therapy was associated with increased survival in diabetic veterans, which was further enhanced when fitness and statin therapy were combined. In addition, statin therapy eliminated the increased mortality risk associated with BMI <25 kg/m(2). The presence of a paradoxical BMI-mortality risk association, which is modulated by statin therapy has novel clinically relevant implications.