PURPOSE: Obesity-related illness is the second-leading preventable cause of death in the United States. As the prevalence of obesity increases, many Americans are turning to very-low-carbohydrate diets to lose weight despite little scientific information regarding efficacy and safety. The purpose of this study was to evaluate the body mass and metabolic effects of a very-low-carbohydrate diet and nutritional supplementation in healthy, overweight individuals. METHODS: Fifty-one overweight (BMI > 25 kg/m2), otherwise healthy individuals (normal history, physical exam and basic laboratory tests) were recruited into this six-month, single-arm, prospective clinical trial. The intervention included dietary counseling based on a popular very-low-carbohydrate (ketone-producing) diet book, group meetings (every other week for 3 months, then monthly for 3 months), daily nutritional supplementation (consisting of vitamins, minerals and oils) and an exercise recommendation. Dietary adherence was monitored by urinary ketone measurement. RESULTS: Forty-one of 51 subjects (80%) attended visits through 16 weeks. This efficacy analysis is based on data from these 41 individuals through 16 weeks. The mean age was 43.7 years (SD = 8.9); 76% were female; 76% were Caucasian, 22% were African-American. At baseline, the mean weight was 87.0 kg (SD = 11.1), BMI was 31.4 kg/m2 (SD = 2.8, range: 25.8 to 39.7 kg/m2), total cholesterol was 214.5 mg/dl (SD = 34.9), LDL was 134.4 mg/dl (SD = 30.4), HDL was 52.5 mg/dl (SD = 13.5), triglycerides were 129.9 mg/dl (SD = 61.9) and total cholesterol/HDL ratio was 4.3 (SD = 1.3). All subjects lost weight after 16 weeks (range: 2.7 to 17.0 kg). Mean weight decreased by 9.7 kg (SD = 3.4, p < 0.001 by paired t-test); mean BMI decreased by 3.5 kg/m2 (SD = 1.2, range: 1.1 to 6.2 kg/m2, p < 0.001). The amount of weight loss positively correlated with level of urinary ketones (p = 0.003). After 16 weeks, there were significant changes in mean total cholesterol of −11.8 mg/dl (p = 0.03), triglycerides of −52.1 mg/dl (p < 0.001), HDL of +4.7 mg/dl (p = 0.006) and total cholesterol/HDL ratio of −0.7 (p < 0.001). There was no statistically significant change in mean LDL. There were no significant changes over 16 weeks in mean serum uric acid (5.1 to 5.2 mg/dl) or creatinine (0.86 to 0.85 mg/dl), but mean BUN increased from 12.7 to 15.9 mg/dl (p < 0.001). There were no clinically significant adverse effects of the diet. CONCLUSION: In this study of healthy, overweight individuals, a very-low-carbohydrate diet with nutritional supplementation led to weight loss of 0.6 kg per week. This dietary approach was efficacious for weight loss while significantly improving total cholesterol, triglycerides, HDL and total cholesterol/HDL ratio.