The objective was to determine whether higher physical activity is associated with lower serum C-reactive protein (CRP), independent of oral hormone replacement therapy (HRT) status and body fatness, in 133 postmenopausal women using a cross-sectional exploratory design at a university research laboratory. The subjects were 133 postmenopausal women, age 50–73 years, with no evidence of coronary artery disease or diabetes. The main outcome measures were: serum CRP, physical activity as measured by Stanford 7-day activity recall, body fat (both total and regional) as measured by dual energy X-ray absorptiometry (DXA), and anthropometry (waist and hip circumference). Secondary outcome measures included fasting plasma glucose and insulin as well as fasting serum triglycerides, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. Higher physical activity energy expenditures were significantly associated with lower serum CRP levels (r = −0.18, P = 0.041), independent of oral HRT use, age, smoking behavior, alcohol consumption, aspirin use, and statin use. However, in the complete multivariate model, which included body fat, older ages (P = 0.047), greater trunk fat masses (P < 0.001), any oral HRT use (P < 0.001), and unopposed oral estrogen use (P = 0.012) were the sole independent predictors of higher serum CRP levels. The complete multivariate model accounted for 58% of the variance in serum CRP. We conclude that the association between higher physical activity and lower serum CRP levels is dependent on the lower body fat of the more active women, yet independent of oral HRT use. Future intervention trials should determine whether diet- and exercise-related reductions in body fat may be effective ways to diminish the proinflammatory effects of oral HRT in postmenopausal women. Am. J. Hum. Biol. 15:91–100, 2003. © 2002 Wiley-Liss, Inc.