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Background: Whether higher cardiorespiratory fitness (CRF) confers protection against cardiovascular disease (CVD) in individuals with manifest hypercholesterolemia is poorly understood. Methods: Participants were 8920 men aged 20–82 years with hypercholesterolemia but no history of CVD and/or cancer and who received a preventive examination at the Cooper Clinic in Dallas, TX, USA, during 1974–2001. CRF was quantified as maximal treadmill test duration and was grouped for analysis as low, moderate, or high based on the traditional Aerobics Center Longitudinal Study cutpoints. Using Cox regression analyses, we computed hazard ratios and 95% confidence intervals for risk of mortality based on CRF. Results: During an average of 17 years of follow-up, 329 CVD and 290 cancer deaths occurred. After control for baseline age, examination year, body mass index, total cholesterol, smoking, alcohol intake, physical activity, hypertension, diabetes, and parental history of CVD, hazard ratios (95% confidence interval) for CVD deaths across moderate and high categories of CRF (with low fit as referent) were: 0.66 (0.50–0.87) and 0.55 (0.39–0.79), respectively. There was an inverse association between CRF and CVD death among normal-weight (trend p < 0.0001), younger (<60 y, trend p = 0.01), and inactive men (trend p = 0.002). However, no significant association was found between CRF and cancer mortality. Conclusions: Among men with hypercholesterolemia, higher CRF was associated with a lower risk of dying from CVD independent of other clinical risk factors. Our findings underscored the importance of promoting CRF in the primary prevention of CVD in patients with hypercholesterolemia. [ABSTRACT FROM AUTHOR]