PURPOSE: The purposes of this study were two-fold: (1) to evaluate the effects of an 8-wk weight loss program on natural killer (NK) cell activity in obese women and 2) to determine whether an additional program of combined aerobic and resistance exercise training modified the effects of caloric restriction on immune function. METHODS: Twenty-two healthy obese women with a mean weight of 96.9 +/- 14 kg and age of 38 +/- 7 yr were randomly assigned to diet-alone (D) or diet-plus-exercise training (D + EX) conditions. Subjects consumed 950 kcal.d-1 using prepackaged portion-controlled foods. Subjects in the D + EX group participated 3 times.wk-1 in a supervised program of light-to moderate-intensity aerobic activity and resistance training. Data were analyzed using a repeated measures ANOVA. RESULTS: After 8 wk of treatment, body weight decreased significantly in both groups (10.8% in D vs 11.4% in D + EX), whereas absolute and relative VO2peak increased in only D + EX (12.3% in D vs 57.7% in D + EX). Both groups experienced significant decreases in peripheral blood leukocytes and lymphocytes, although cell numbers remained within clinically normal range at week 8. NK cell (CD56+) proportion was unchanged in both groups after weight loss. The proportion of peripheral mononuclear cells expressing the interleukin-2 receptor-alpha (IL-2R alpha) (CD25+) decreased significantly (25.2%) in D and was unchanged in D + EX, resulting in a significant difference between groups at week 8. NK cell cytotoxicity was suppressed in D and unchanged in D + EX after treatment. Changes in NK cell activity were significantly correlated with proportional changes in (CD25+) (r = 0.584, P = 0.022), but not CD56+. CONCLUSIONS: A combined program of light- to moderate-intensity aerobic and resistance exercise offsets the apparent decrement in NK cell activity associated with weight loss.