PURPOSE: To determine the associations of muscular strength (MS) with cardiovascular disease (CVD) and all-cause mortality in adults with hypercholesterolemia. METHODS: Participants comprised 1,925 adults aged ≥40 years (mean age 50) who had a medical examination during 1980-1990 in the Aerobics Center Longitudinal Study. They were free of CVD, cancer, had ≥85% of their age-predicted maximal heart rate on a treadmill test, and hypercholesterolemia at baseline. MS was measured by 1 repetition maximums of bench and leg presses and a composite MS score was computed by combining the standardized values of both tests. Cardiorespiratory fitness (CRF) was estimated from a maximal treadmill test. We used tertiles of the sex- and age-specific total MS scores. Further, MS and CRF were dichotomized into either weak (lower one-third) or unfit (lower half), or strong (upper two-thirds) or fit (upper half) in a joint analysis of MS and CRF with mortality. Mortality follow-up was through 2003 using the National Death Index. Cox regression models included baseline age, sex, examination year, body mass index, smoking, alcohol intake, physical activity, parental CVD, hypertension, diabetes, abnormal electrocardiogram, total cholesterol, and CRF. RESULTS: During an average follow-up of 18 years, 67 CVD and 172 all-cause deaths occurred. Compared with lower MS group, the hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD and all-cause mortality were 0.45 (0.24-0.85) and 0.58 (0.40-0.85) in middle MS group ,respectively, and 0.46 (0.25-0.86) and 0.63 (0.43-0.93) in upper MS group, respectively, after adjusting for confounders including CRF. We found similar trends in both men and women, and normal weight and overweight or obese adults. In the joint analysis, compared with unfit and weak group, HRs (95% CIs) for CVD and all-cause mortality were 0.41 (0.22-0.78) and 0.41 (0.27-0.62) in unfit and strong group, respectively; 0.70 (0.30-1.66) and 0.60 (0.34-1.08) in fit and weak group, respectively; and 0.39 (0.19-0.82) and 0.59 (0.39-0.90) in fit and strong group, respectively. CONCLUSIONS: MS, independent of CRF, should be promoted as a predictor of CVD and all-cause mortality in adults with hypercholesterolemia who are at increased mortality risk. Supported by NIH Grant AG06945, HL62508, DK088195, and HL133069.