Rodent experiments raise the possibility of a regulatory role of peripheral α-melanocyte-stimulating hormone (α-MSH) in obesity and metabolism, but human data on peripheral α-MSH levels remain fragmentary. Because of the possible relationship between α-MSH and obesity, we endeavored to test the hypothesis that higher levels of α-MSH in obese patients would correlate with leptin levels and with other markers of obesity. Sixty normal-weight to obese healthy men and women participated. Weight, measures of body composition, and diet diaries were obtained; fasting blood was analyzed for α-MSH, lipids, glucose, insulin, leptin, and adiponectin. To begin to understand the source of peripherally measured hormones, α-MSH was also measured in serum samples from 5 individuals with untreated Addison disease. Levels of α-MSH were higher in men vs women (10.1 ± 4.3 vs 7.6 ± 3.4 pmol/L, P = .019), and α-MSH levels were higher in patients with Addison disease vs controls (17.7 ± 2.3 vs 8.7 ± 0.52 pmol/L, P < .001). Measures of adiposity correlated with insulin and leptin in men and women, and with adiponectin in women. α-Melanocyte-stimulating hormone levels did not correlate significantly with any parameter of adiposity or diet composition. The elevated α-MSH levels in patients with untreated Addison disease suggest possible pituitary secretion of α-MSH to the periphery. The lack of correlation between peripheral α-MSH and parameters of adiposity suggests that endogenous plasma α-MSH levels are not a metric for body composition per se.