Leptin is a recently discovered peptide hormone secreted primarily from adipocytes in humans and other mammals; it is a reflection of fat stores, and has been associated with reproductive function. However, few leptin measurements are available from nonindustrialized populations, including contemporary hunter/gatherer communities undergoing the transition to sedentary agriculture. This investigation reports single-sample serum leptin measurements in healthy Ache Amerindian males (n = 21; average age, 32.8 ± 3.4 SE) and females (n = 12; average age, 31.3 ± 4.3) in eastern Paraguay. Ache leptin concentrations were much lower than in industrialized populations, although significant sexual dimorphism was evident (female 5.64 ng/ml ± 0.91 SE vs. male 1.13 ng/ml ± 0.08; P < 0.0001). Indeed, female leptin levels were similar to those of anorexic women, despite apparently adequate adiposity. Controlling for fat percentage, no significant sex difference was evident, suggesting that adiposity was the primary source of leptin variation. Body fat percentage was highly correlated with leptin in females (r2 = 0.72; P < 0.0005) but not males, who exhibited a modest negative correlation (r2 = 0.25; P < 0.03). Weight (r2 = 0.45; P = 0.02) and BMI (kg/m2) (r2 = 0.81; P < 0.0001) were also significantly correlated in females but not males. These results suggest that: 1) clinical leptin norms based on industrialized populations may represent the highest range of human variation and may not be representative of most human populations; 2) hormonal priming may underlie population variation in leptin profiles; and 3) the relative importance of leptin as a proximate mechanism regulating reproductive effort during human evolution may have been modest. Am J Phys Anthropol 115:297–303, 2001. © 2001 Wiley-Liss, Inc.