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A robust literature demonstrates that coronary artery calcification (CAC) and cardiorespiratory fitness (CRF) are independent predictors of cardiovascular disease (CVD) events. Much less is known about the joint associations of CRF and CAC with CVD risk. In the setting of high CAC, high versus low CRF has been associated with decreased CVD events. The goal of this study was to assess the effect of continuous levels of CRF on CVD risk in the setting of increasing CAC burden.We studied 8425 men without clinical CVD who underwent preventive medicine examinations that included an objective measurement of CRF and CAC between 1998 and 2007. There were 383 CVD events during an average follow-up of 8.4 years. Parametric proportional hazards regression models based on a Gompertz mortality rule were used to estimate total CVD incidence rates at 70 years of age as well as hazard ratios for the included covariates.CVD events increased with increasing CAC and decreased with increasing CRF. Adjusting for CAC level (scores of 0, 1–99, 100–399, and ≥400), for each additional MET of fitness, there was an 11% lower risk for CVD events (hazard ratio, 0.89; 95% confidence interval, 0.84-0.94). When CAC and CRF were considered together, there was a strong association between continuous CRF and CVD incidence rates in all CAC groups.In a large cohort of generally healthy men, there is an attenuation of CVD risk at all CAC levels with higher CRF.