Although obesity is a risk factor for mortality, it is unclear whether waist circumference (WC) is a better predictor of mortality than BMI in a clinical setting of patients at high risk for coronary artery disease (CAD). Thus, we compared the association between WC and BMI with all-cause mortality in relation to traditional CAD risk factors in a high-risk cohort. Study population included 5,453 consecutive new patients seen between 1996 and 2005 for management of CAD risk factors in a preventive cardiology clinic. Mortality was determined from the Social Security Death Index. There were 359 deaths over a median follow-up of 5.2 years. Mortality was greater in high (>102 cm in men and >88 cm in women) vs. normal WC in both genders (P < 0.01). The unadjusted Cox proportional hazard ratio (HR) for continuous WC (per cm) was 1.02 (P < 0.001) in both genders and remained significant after adjustment for CAD risk factors (HR = 1.01 in men, HR = 1.03 in women, both P < 0.05). BMI did not associate statistically with mortality. WC associated with diabetes mellitus (DM) and CAD prevalence (P < 0.001). BMI associated only with DM (P < 0.001) and this association disappeared when WC was added to the model. We conclude that WC is an independent predictor of all-cause mortality in a preventive cardiology population. These data affirm the clinical importance of WC measurements for mortality, DM, and CAD risk prediction and suggest that obesity-specific interventions targeting WC in addition to traditional risk factor management may favorably impact these outcomes.