Background: HMG-CoA reductase inhibitors (statins) are among the most commonly prescribed classes of medications. Although their cardiovascular benefits and myalgia risks are well documented, their effects on older adults initiating an exercise training program are less understood. Methods: 1,635 sedentary men and women aged 70-89 years with Short Physical Performance Battery (SPPB) score of 9 or below and were able to walk 400 m were randomized to a structured, moderate-intensity physical activity (PA) program consisting of both center-based (twice/wk) and home-based (3-4 times/wk) aerobic, resistance, and flexibility training or to a health education (HE) program combined with upper extremity stretching. Results: Overall, the PA intervention was associated with lower risk of major mobility disability (hazard ratio [HR] = 0.82; 95% confidence interval [CI] = 0.69-0.98). The effect was similar (p value for interaction =. 62) in both statin users (PA n = 415, HE n = 412; HR = 0.86, 95% CI = 0.67-1.1) and nonusers (PA n = 402, HE n = 404; HR = 0.78, 95% CI = 0.61-1.01). Attendance was similar for statin users (65%) and nonusers (63%). SPPB at 12 months was slightly greater for PA (8.35±0.10) than for HE (7.94±0.10) in statin users but not in nonusers (PA 8.25±0.10, HE 8.16±0.10), though the interaction effect was not statistically significant. Self-reported PA levels were not different between statin users and nonusers. Conclusions: Although statins have been associated with adverse effects on muscle, data from the LIFE Study show that statin users and nonusers both benefit from PA interventions. Older adults who require statin medications to manage chronic medical conditions and are sedentary will be able to benefit from interventions to increase PA.