The purpose of this study was to determine whether a hypocaloric diet with and without exercise training is effective in reducing plasma C-reactive protein, IL-6, TNFα, and their soluble receptors (sIL-6R, sTNFR1, and sTNFR2), and whether changes in these inflammatory markers are related to changes in regional lipolysis in obese (body mass index, 32.78 ± 4.73) postmenopausal women (diet alone, n = 17; diet plus exercise, n = 17). All inflammatory markers were measured by an ELISA method. In vitro lipolysis was evaluated by measuring glycerol release using a one-step enzymatic fluorometric technique. Six months of diet and diet plus exercise decreased total and abdominal fat to a similar degree. Diet plus exercise, but not diet alone, decreased plasma levels of C-reactive protein, IL-6, sIL-6R, and sTNFR1 and increased basal and postreceptor stimulated lipolysis in both abdominal and gluteal regions. Changes in abdominal stimulated lipolysis correlated significantly with changes in plasma IL-6 (r = −0.39) and TNFR1 (r = −047). Thus, diet plus exercise training, but not diet alone, is effective in reducing chronic inflammation in obese postmenopausal women. In addition, modification of chronic inflammation is associated with changes in local adipose tissue metabolism in response to diet and exercise.