OBJECTIVE: Determine whether the independent inter-relationships between intra-abdominal adipose tissue (IAF), cardiovascular disease (CVD) risk, and physical activity (PA) support the hypothesis that the beneficial effect of PA on CVD risk is mediated through the effects of activity on IAF. DESIGN: Cross-sectional. SUBJECTS: 220 female Caucasian women 17-77 years old. MEASUREMENTS: Computed tomography IAF and subcutaneous abdominal adipose tissue (SAF), percent fat, CVD risk factors (blood lipids and blood pressure) and PA using the Baecke questionnaire. RESULTS: Zero-order correlations indicated that IAF, SAF, percent fat, age, menopausal status (MS), and all 4 of the PA indexes were consistently related to CVD risk. After adjusting for age, MS, SAF, and percent fat, IAF was negatively related to PA (r2 = 0.04), indicating that more active women had relatively small IAF compared to other fat depots. After adjusting for IAF, MS, and age none of the PA indexes were related to any of the CVD risk factors except cholesterol/HDL ratio (partial r2 = 0.02). However, after adjusting for PA, MS and age, IAF was related to ail CVD risk factors except cholesterol (partial r2 = 0.03-0.23). CONCLUSION: These results support the hypothesis that PA may obtain at least part of its effect on CVD risk by reducing IAF.