The serum prostate specific antigen (PSA) level was determined in 311 men with documented prostate cancer (stages T1cN0, T2N0 and T3N0) before bilateral pelvic lymphadenectomy and radical retropubic prostatectomy. The prostates were whole mounted, serially sectioned, and examined for cancer volume, capsular perforation, seminal vesicle invasion, lymph node involvement, Gleason grade, nuclear grade and nuclear deoxyribonucleic acid content. Median serum PSA level was significantly different between cancers that were organ confined, those that had capsular perforation or seminal vesicle invasion and those with positive lymph nodes (p < 0.001). Median serum PSA level was also significantly different between tumors with Gleason scores of less than 6 and those with higher Gleason scores (p < 0.001), and between tumors with greater than 30% of poorly differentiated cancer (Gleason primary grades 4 and 5) and those with 30% or less poorly differentiated cancer (p < 0.001). Bivariate analysis revealed that the strongest correlations of serum PSA level were with cancer volume (r = 0.56), per cent of poorly differentiated cancer (r = 0.42), positive surgical margins (r = 0.39) and pathological stage (r = 0.38), for all p < 0.001. Multivariate analysis showed that cancer volume was the major contributor to serum PSA level. The derivative, PSA-cancer density (serum PSA times cancer volume divided by prostate volume), accounted for the effects of prostate volume and cancer volume on serum PSA. PSA-cancer density showed a significant correlation with pathological stage (r = 0.56), Gleason score (r = 0.53) and per cent of poorly differentiated cancer (r = 0.49, for all p < 0.001), and these correlations were significantly stronger than serum PSA level alone or PSA density (serum PSA divided by prostate volume; volume determined from tissue specimens) for all variables. These results indicate that preoperative serum PSA level has significant predictive value in determining tumor burden and pathological stage, and this predictive value is increased by accounting for cancer and gland volume with PSA-cancer density.