Obesity is an important risk factor for hypertension; however, the pathway through which it raises blood pressure (BP) is poorly understood. Body size is also the primary determinant of energy expenditure, and we therefore examined the joint relationship of energy expenditure and body size to blood pressure. Resting energy expenditure (REE) was measured using respiratory gas exchange in population-based samples of 997 Nigerians and 452 African Americans. In a third sample of 118 individuals, nonresting energy expenditure (ie, physical activity) was measured in addition to REE. The univariate correlation between REE and BP ranged from 0.10 to 0.22 in the 3 samples (P<0.001). In multivariate models, adiposity, whether defined by body mass, fat mass, or leptin, was no longer associated with BP, while REE remained highly significant (P<0.001). The REE-BP association also persisted after adjustment for physical activity measured with doubly labeled water. The odds ratio for hypertension among persons in the highest quartile versus the lowest quartile of REE, after adjustment for body size, was 1.7. This relationship was not the result of hypertension among the obese, because it did not vary across the range of BMI and was the same in lean Nigerians as in obese Americans. These data suggest that metabolic processes represented by REE may mediate the effect of body size on BP. The interrelationship of REE with sympathetic tone, transmembrane ion exchange, or other metabolic processes that determine energy costs at rest could provide physiological explanations for this observation.