Background: Studies have found that higher levels of cardiorespiratory f?tness and light to moderate alcohol intake reduce the risk for premature death. Scant evidence, however, exists assessing the joint effects of both measures on all-cause and cardiovascular disease (CVD) mortality. Purpose: This study aims to examine the independent and joint effects of alcohol consumption and cardiorespiratory f?tness on all-cause and cardiovascular-related mortality in a large cohort of men. Methods: This prospective study included 29,402 men who came to the Cooper Clinic (Dallas, TX) for a preventive medicine visit from 1973 to 2006. Data were analyzed in 2011. The primary exposure variables were tertiles of cardiorespiratory f?tness and four categories of alcohol consumption, and the outcomes were all-cause and CVD mortality. Cox proportional hazards regression was used to model the association between alcohol intake, cardiorespiratory f?tness, and all-cause and CVD mortality, controlling for potential confounders. Results: A total of 1830 (all-cause) and 523 (CVD) deaths occurred in men over an average follow-up period of 17.4 years (SD=9.1). A linear relationship was observed (p<0.001) between increased f?tness and reduced all-cause and CVD mortality. Specif?cally, moderate and high levels of f?tness reduced the risk for all-cause mortality (HR=0.67, 95% CI=0.60, 0.74, and HR=0.57, 95% CI=0.49, 0.67, respectively) and CVD mortality in comparison to the low-f?tness reference group (HR=0.70, 95% CI=0.57, 0.85; HR=0.54, 95% CI=0.40, 0.75, respectively), while controlling for alcohol intake and other covariates. A signif?cant curvilinear relationship was found (p=0.01) between alcohol intake and all-cause mortality (but not CVD mortality), while controlling for f?tness and other covariates. In a categoric examination of alcohol intake and mortality, adjusting for f?tness and other confounders, there was no statistically signif?cant effect of light drinking compared to heavy drinking on all-cause mortality or CVD mortality. An examination of the joint effects of f?tness and alcohol on all-cause mortality showed that moderate and high f?tness levels were protective against mortality irrespective of alcohol consumption levels. Few signif?cant combined effects for CVD mortality reduction were found. Conclusions: Alcohol consumption did not signif?cantly modify the association between f?tness and mortality in this large cohort of men. © 2012 American Journal of Preventive Medicine.