Obesity and type 2 diabetes mellitus (T2DM) have been associated with a state of chronic low-grade inflammation. We examined the effect of exercise without weight loss on circulating inflammatory biomarkers in previously sedentary lean men and obese men with and without T2DM. Middle-aged men (8 lean, 8 obese, and 8 obese with T2DM) performed 60 minutes of aerobic exercise 5 times per week for 12 weeks without a reduction in body weight. Subjects underwent a hyperinsulinemic-euglycemic clamp before and after the 12-week exercise program to assess insulin sensitivity. Circulating interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), and C-reactive protein concentrations were measured by sandwich enzyme-linked immunosorbent assay before and after the exercise intervention. Body fat was measured using magnetic resonance imaging, and waist circumference was recorded for each subject pre- and postexercise intervention. Waist circumference and plasma IL-6 concentrations were significantly lower (P < .05) after exercise training despite no change in body weight or insulin sensitivity. There were no correlations between insulin sensitivity and IL-6. Fasting plasma PAI-1 concentration was significantly lower in the lean group compared with the obese group both pre- and postexercise intervention (P < .05). There were no changes in C-reactive protein or PAI-1 concentrations after exercise training. A 12-week exercise intervention led to reductions in waist circumference and fasting IL-6 concentrations in previously sedentary lean and obese men with or without T2DM, demonstrating significant changes in clinically relevant diabetes-related parameters despite no change in body weight.