Several studies have reported a positive relation of baseline body mass index (BMI) with multiple myeloma, but data on other correlates of energy balance are limited. We undertook the present analyses to further examine the role of energy balance in multiple myeloma etiology in two large prospective cohorts with biennially updated exposure data. We followed members of the Nurses' Health Study and Health Professionals Follow-up Study cohorts from baseline until multiple myeloma diagnosis, death, or 2002. Adult height and current weight were reported at enrollment, and weight every 2 years thereafter. Physical activity was queried at baseline and updated every 2 to 4 years. We computed age-adjusted relative risks (RR) of multiple myeloma for categories of BMI and physical activity using Cox proportional hazards regression. We conducted analyses on each cohort separately and on both cohorts combined. We confirmed 215 incident cases of multiple myeloma in the combined cohort of 136,623 individuals (>2.1 million person-years at risk). BMI was positively associated with multiple myeloma in all analyses. The association was strongest in men with a BMI of >or=30 kg/m2 (versus a BMI of <22.0 kg/m2; RR, 2.4; 95% confidence interval, 1.0-6.0) and modest in overweight (BMI, 25-29.9 kg/m2) and obese (BMI, >or=30 kg/m2) women [versus BMI of <22.0 kg/m2; RR (95% confidence interval), 1.6 (1.0-2.7) and 1.2 (0.7-2.2), respectively]. Physical activity was not significantly related to multiple myeloma risk, although an inverse association was suggested in women. In conclusion, obesity seems to have an etiologic role in multiple myeloma, but the role of other correlates of energy balance remains uncertain.