There are competing theories explaining the observed inverse association between obesity and screening prostate-specific antigen (PSA) levels: (a) endocrine disturbances related to abdominal obesity influence PSA production and (b) increased plasma volume associated with obesity dilutes PSA. Under the endocrine disturbance hypothesis, fat mass, but not lean mass, and an abdominal distribution of fat are expected to be inversely associated with PSA levels. Under plasma volume dilution theory, PSA levels are inversely associated with both lean and fat mass and are independent of body fat distribution patterns. Data on weight, percent body fat measured by bioimpedance, and waist circumference from approximately 8,000 men undergoing routine PSA screening were evaluated. Multivariate linear regression analyses controlling for age and race/ethnicity were used to determine whether fat, lean mass, or waist circumference were associated with PSA. PSA levels were significantly inversely associated with both lean and fat mass. In separate models, a 5-pound difference in lean mass and fat mass was associated, respectively with a -0.9% (P < 0.001) and -0.7% (P = 0.001) difference in PSA test results. In a model that simultaneously considered lean and fat mass, a 5-pound difference in lean mass and fat mass was associated, respectively, with a -0.6% (P = 0.03) and -0.4% (P = 0.08) difference in PSA test results. Controlling for body mass index, a 1-inch difference in waist circumference was associated with a +0.9% (P = 0.01) difference in PSA levels. The results are more consistent with predictions arising from the volume dilution theory than the hormone disturbance theory.