Objective: To determine if a missense change at codon 64 of ADRB3 (Trp64Arg), a candidate obesity gene, is associated with obesity and levels of subcutaneous or visceral fat in African-American breast cancer cases. Several observational studies have found that women, who are overweight or obese at the time of diagnosis, as well as those who gain weight after diagnosis, are at greater risk for breast cancer recurrence and death than non-overweight women. Design: Prospective cohort of breast cancer cases. Subjects: 219 African-American breast cancer patients participating in the Los Angeles component of the Health, Eating, Activity and Lifestyle Study. Measures: ADRB3 Trp64Arg genotype, measures of weight including body mass index (BMI), weight gain (weight 5 years before diagnosis compared with weight at 30 months after diagnosis), obesity (BMIX30 kg/m 2 ), waist/hip circumference and visceral or subcutaneous fat were determined by magnetic resonance imaging. Results: African-American women who were homozygous for the ADRB3 wild-type allele had significantly higher mean visceral fat levels than women who carried the variant (P ¼ 0.04), and were significantly more likely to be obese (odd ratios (OR) ¼ 2.1, 95% confidence interval (CI) ¼ 1.1-4.2). The association with obesity was most pronounced among women who were premenopausal (OR ¼ 4.8, 95% CI ¼ 1.3-18), who received chemotherapy for their breast cancer (OR ¼ 6.1, 95% CI ¼ 1.8-20), or who were not physically active (OR ¼ 3.9, 95% CI ¼ 1.5-9.7). Conclusion: The wild-type allele of the ADRB3 missense change was associated with measures of obesity in our sample of African-American women. The association was modified by menopausal status, history of chemotherapy and modest levels of physical activity. These results will need to be confirmed in an independent sample.