While there is evidence that breast cancer risk is positively associated with body mass index (in postmenopausal women) and energy intake and inversely associated with physical activity, few studies have examined breast cancer risk in association with energy balance, the balance between energy intake and expenditure. Therefore, in the cohort study reported here, we studied the independent and combined associations of vigorous physical activity, energy consumption, and body mass index (BMI), with breast cancer risk. The investigation was conducted in 49,613 Canadian women who were participants in the National Breast Screening Study (NBSS) and who completed self-administered lifestyle and food frequency questionnaires between 1980 and 1985. Linkages to national mortality and cancer databases yielded data on deaths and cancer incidence, with follow-up ending between 1998 and 2000. During a mean 16.4 years of follow-up, we observed 2545 incident breast cancer cases. Due to exclusions for various reasons, the analyses were based on 40,318 subjects amongst whom there were 1673 incident cases of breast cancer. Participation in vigorous physical activity and body mass index were not independently associated with breast cancer risk in the total cohort. A statistically significant positive trend was observed, however, between energy intake and breast cancer risk (P (trend )= 0.01). Although there was some variation in risk associated with vigorous physical activity, and BMI when the analyses were stratified by menopausal status, these interactions were not statistically significant. The interaction between menopausal status and energy intake, however, was of borderline statistical significance (P (interaction )= 0.06), with a statistically significant increased risk of breast cancer associated with highest versus lowest quartile of energy intake among premenopausal women (Hazard Ratio [HR] = 1.45, 95% confidence interval [CI] = 1.13- 1.85, P (trend) = 0.001). There was evidence of an increased risk of breast cancer associated with a relatively high body mass index among postmenopausal women in the highest quartile level of energy intake (Hazard Ratio [HR] = 1.72, 95% confidence interval [CI] = 1.01- 2.93, P (trend) = 0.05). In addition, there was evidence of an increased risk of breast cancer among premenopausal, physically inactive, overweight/obese women who consumed > or =1972 kcal/day compared to physically active normal weight women who consumed <1972 kcal/day (HR = 1.60, 95% CI = 1.08-2.37). Our data suggest that obese premenopausal women with relatively high energy intake may be at increased risk of breast cancer. In addition, energy imbalance, represented by a relatively high energy intake, lack of participation in vigorous physical activity, and a relatively high body mass index, may be associated with increased breast cancer risk, particularly among premenopausal women.