The independent effects of exercise and weight loss on markers of inflammation (MOI) in obese individuals have not been clearly characterized. The objectives of this study were to: (i) identify the independent effects of exercise and weight loss on MOI and (ii) determine whether changes in MOI were associated with changes in fat distribution. Subjects were 126 healthy, premenopausal women, BMI 27-30 kg/m(2). They were randomized to one of three groups: diet only, diet + aerobic-, or diet + resistance training until a BMI <25 kg/m(2) was achieved. Fat distribution was measured with computed tomography, and body composition with dual-energy X-ray absorptiometry. Serum concentrations of tumor necrosis factor (TNF)-α, soluble TNF receptor 1 (sTNF-R1), soluble TNF receptor 2 (sTNF-R2), C-reactive protein (CRP), and interleukin (IL)-6 were assessed. Results of repeated-measures ANOVA indicated a significant effect of time on MOI, such that MOI decreased with weight loss. Results of mixed-model analysis indicated that adjusting for intra-abdominal adipose tissue (IAAT) and total fat mass explained the decreases in TNF-α and sTNF-R1, whereas only total fat mass explained the decreases in sTNF-R2, IL-6, and CRP. In conclusion, weight loss was associated with decreases in MOI. The effect of weight loss appeared to be mediated by changes in total fat mass or IAAT. Addition of exercise did not alter the response, suggesting that weight loss has a more profound impact for reducing MOI in overweight women than exercise.