PURPOSE: Previous studies have shown that weight loss via dietary restriction results in undesirable changes in mood, metabolic rate, and hormone profile. This study examined the effects of a combined diet/exercise/supplement weight loss regimen on mood state and metabolic parameters. METHODS: We recruited 32 moderately overweight men and women to participate in a 12-week program of stress management, nutrition intervention, exercise, and dietary supplementation. Subjects followed a moderate calorie-restricted diet based on resting metabolic rate (RMR), plus a moderate exercise program (3 d/wk aerobic & 2 d/wk strength training), stress management techniques (daily) and a non-commercial herbal dietary supplement (daily) intended to improve mood and increase energy levels. We measured body weight (BW), RMR, body fat (BF by BIA), cortisol and testosterone (C and T by salivary enzyme immunoassay), total cholesterol (TC), LDL, HDL, glucose (G), triglycerides (TG), and global mood state (MOOD by Profile of Mood States) before and after the 12-week lifestyle intervention. RESULTS: Twenty-nine subjects completed the program (9% attrition rate), suggesting that the program was easy to follow and not overly restrictive. The overall lifestyle program led to significant changes in BW, BF, T, TC, LDL, and MOOD (all p<0.05 by paired t-test compared to baseline values). Additionally, indexes of depression and fatigue were reduced by 52% and 48%, respectively (both, p<0.05), indicating a significantly improved mood after 12 weeks. RMR, C, HDL, G, and TG were unchanged. CONCLUSIONS: These data indicate that a weight loss dietary regimen in conjunction with aerobic and resistance exercise and a daily dietary supplement prevents the expected decline in fat-free mass and resting metabolic rate - and results in favorable changes in body composition, metabolic hormones, mood, and cardiovascular parameters. The low attrition rate and reduced indexes of depression and fatigue suggest that effective weight loss and lifestyle regimens need not be overly restrictive, and thus, may be expected to result in superior long-term adherence and, possibly, better maintenance of weight loss.