ObjectiveTo investigate the concurrent relationships between human plasma erythropoietin concentrations and energy expenditure (EE), body composition, plasma leptin concentrations, and associations with weight change.MethodsPlasma to measure erythropoietin and leptin; data for body composition; 24‐h EE measured in a whole‐room calorimeter; and 75 g oral glucose tolerance testing were available from 109 full‐heritage Pima Indians (55% male) from a larger study designed to understand the causes of obesity. Seventy‐nine subjects had data for weight at a later visit (mean follow‐up=4.3 ± 1.9 years) to calculate percent weight change per year.ResultsErythropoietin, adjusted for covariates, correlated with 24‐h EE (r =0.26,P =0.007), sleeping EE (r =0.29,P =0.003), fat‐free mass (r =0.19,P =0.05), and fat mass (r =0.27,P =0.005), but not insulin or glucose measures. The association of erythropoietin with 24‐h EE was fully mediated by fat‐free mass. Erythropoietin associated with leptin in women (ρ = 0.36,P =0.01), but not in men (P =0.9), independently from fat mass. The association of erythropoietin with percent weight change per year was in opposing directions (interaction:P =0.002) in males (r =−0.35,P =0.02) versus females (r =0.37,P =0.02).ConclusionsNon‐hematopoietic endogenous erythropoietin action may be involved in body weight regulation in opposing directions in men and women, i.e., weight loss in men and weight gain in women.