To compare the effects of weight loss vs aerobic exercise training on coronary artery disease risk factors in healthy sedentary, obese, middle-aged and older men. Randomized controlled trial. A total of 170 obese (body mass index, 30 +/- 1 kg/m2 [mean +/- SEM]), middle-aged and older (61 +/- 1 years) men. A 9-month diet-induced weight loss interventions, 9-month aerobic exercise training program, and a weight-maintenance control group. Change in body composition, maximal aerobic capacity (V02 max), blood pressure, lipoprotein concentrations, and glucose tolerance. Forty-four of 73 men randomized to weight loss completed the intervention and had a 10% mean reduction in weight (- 9.5 +/- 0.7 kg; P < .001), with no 22 change in VO2 max. Forty-nine of 71 men randomized to aerobic exercise completed the intervention, increased their VO2 max by a mean of 17% (P < .001), and did not change their weight, whereas the 18 men who completed in the control group had no significant changes in body composition or VO2 max. Weight loss decreased fasting glucose concentrations by 2%, insulin by 18%, and glucose and insulin areas during the oral glucose tolerance test (OGTT) by 8% and 26%, respectively (P < .01). By contrast, aerobic exercise did not improve fasting glucose or insulin concentrations or glucose responses during the OGTT but decreased insulin areas by 17% (P < .001). In analysis of variance, the decrement in fasting glucose and insulin levels and glucose areas with intervention differed between weight loss and aerobic exercise when compared with the control group (P < .05). Similarly, weight loss but not aerobic exercise increased high-density lipoprotein cholesterol levels (+ 13%) and decreased blood pressure compared with the control group. In multiple regression analyses, the improvement in lipoprotein and glucose metabolism was related primarily to the reduction in obesity. These results suggest that weight loss is the preferred treatment to improve coronary artery disease risk factors in overweight, middle-aged and older men.