The relationship between obesity and prostate cancer remains unclear. We investigated the effect of prostate volume on the obesity and prostate cancer association. With a multi-centered, rapid-recruitment protocol, weight and body size measurements were collected prior to diagnosis, and medical charts were reviewed for pathology results (n = 420 controls, 119 high-grade prostatic intraepithelial neoplasia (PIN) cases, and 286 cancer cases (41% Gleason > 6). In multivariable logistic regression models adjusting for age, PSA levels and history, DRE results, and number of cores at biopsy, the association between BMI and cancer was restricted to men with a smaller prostate volume (volume < 40 cm(3): ORBMI >= 30 = 2.17 (1.09, 4.32), p(trend) = 0.02; volume >= 40 cm(3): ORBMI >= 30 = 0.77 (0.34, 1.77), p(trend) = 0.17; p (interaction) = 0.03). Similarly, the WHR and PIN association was significantly modified by prostate volume (volume < 40 cm(3): OR(WHR: Tertile 3 vs. T1) = 3.76 (1.54, 9.21) (p(trend) < 0.01); volume >= 40 m(3): OR(WHR: T3 vs. T1) = 0.63 (0.32, 1.23) (p(trend) = 0.17); p(interaction) < 0.01). In conclusion, prostate volume acts as a modifier, and BMI and WHR are significantly associated with prostate cancer or PIN, respectively, in the absence of biopsy sampling error derived from obesity-related prostate enlargement.