The authors investigated the relation between physical activity and cardiovascular disease (CVD) in women by following 1,564 University of Pennsylvania alumnae (mean age, 45.5 years), initially free of CVD, from 1962 until 1993. Energy expenditure was estimated from the daily number of flights of stairs climbed and blocks walked as well as the sports played and was categorized into approximate thirds (<500, 500-999, > or = 1,000 kcal/week). During 35,021 person-years, 181 CVD cases were identified. After adjustment for coronary risk factors, the relative risks of CVD were 0.99 (95% confidence interval (CI): 0.69, 1.41) and 0.88 (95% CI: 0.62, 1.25) for women who expended 500-999 and > or = 1,000, respectively, compared with <500 kcal/week (p for trend = 0.45). Only walking was found to be inversely related to CVD risk (p for trend = 0.054). Compared with women who walked <4 blocks/day, the relative risks of CVD were 0.84 (95% CI: 0.59, 1.19) and 0.67 (95% CI: 0.45, 1.01) for women who walked 4-9 and > or = 10 blocks/day, respectively. Finally, an interaction (p = 0.023) between body mass index and physical activity on CVD risk was observed, with an inverse association only for leaner (<23 kg/m2) women. These data showed no overall association of physical activity with CVD risk in women. However, walking > or = 10 blocks/day (approximately 6 miles (9.7 km)/week) was associated with a 33% decreased risk. One explanation for this finding may be that walking was reported more precisely than other kinds of activities.