This study examined the independent and combined effects of diet and exercise on adipocytokine and inflammatory cytokines in postmenopausal women with type 2 diabetes. Using a randomized, controlled design, 33 women (age, 50-70 years) were assigned to diet alone (D), exercise alone (EX), or diet + exercise (D + E) for 14 weeks. Before and after the interventions, blood samples for adipocytokines and inflammatory markers were drawn, a meal test was performed, and abdominal fat distribution was measured by magnetic resonance imaging (MRI). Body weight decreased ∼4.5 ± 0.6 kg (P < .05) after the D and D + E interventions, whereas only small changes in body weight were found with the exercise-alone intervention. Plasma C-reactive protein levels were decreased by ∼15% with all 3 interventions, whereas leptin levels were reduced with the D and D + E intervention (D: pre = 48.7 ± 6.0, post = 38.9 ± 5.0 ng/mL; D + E: pre = 38.5 ± 6.0, post = 22.9 ± 5.0 ng/mL; P < .05) with no differences between groups. There was a trend for leptin levels to decrease in the EX group (P = .06). Plasma resistin levels were not altered by the 3 interventions from pre- to posttreatment (D: pre = 6.9 ± 0.6, post = 6.2 ± 0.4 ng/mL; D + E: pre = 5.6 ± 0.6, post = 5.7 ± 0.4 ng/mL; E: pre = 6.2 ± 0.6, post = 5.9 ± 0.6 ng/mL, P > .05), and no differences in adiponectin and tumor necrosis factor α (TNF-α) levels were found. Visceral adipose tissue and tumor necrosis factor α were the only predictors of calculated insulin resistance (P < .05), explaining 43% of the variability. A typically prescribed weight loss program with lifestyle changes resulted in few changes in adipocytokines and inflammatory cytokines in older women with type 2 diabetes, suggesting that dramatic weight loss or clinical interventions are needed.