Clinical outcome is variable in prostate cancer patients with regional lymph node metastasis. We studied 269 patients who had regional lymph node metastasis at the time of radical retropubic prostatectomy and bilateral pelvic lymphadenectomy at the Mayo Clinic between January 1987 and December 1992. Two hundred fifty-three (94%) patients received androgen deprivation therapy within 90 days of radical prostatectomy. Patients ranged in age from 47 to 79 years (median, 67 years). Median follow-up was 6.1 years (range, 0.3-10.5 years). Nodal cancer volume (size) was measured by the grid-counting method. Cox proportional hazards models were used to determine the impact of numerous clinical and pathologic findings on systemic progression-free survival. Systemic progression was defined as the presence of distant metastasis documented by biopsies or radiographic examinations (abdominal computerized tomography, plain radiographs, or bone scan). Five-year progression-free survival was 90%. In predicting systemic progression using Cox multivariate analysis, only nodal cancer volume added significantly to the model containing the primary cancer variables (Gleason score, cancer volume, and DNA ploidy). The relative hazard rate for a doubling in nodal cancer volume was 1.6 (95% confidence interval, 1.3 to 2.0; p < 0.0001). Spearman rank analysis showed a correlation between nodal cancer volume and Gleason score of the primary cancer, the number of positive nodes, the aggregate length of metastases, and the largest nodal cancer diameter (correlation efficient = 0.37, 0.63, 0.96, and 0.95, respectively). Our data indicate that nodal cancer volume was the most significant nodal determinant of progression to distant metastasis in lymph node-positive prostate cancer patients. We recommend that the diameter of the largest metastasis be evaluated in patients with metastases, because this is a more powerful predictor of patient outcome than current methods, which recommend mere counting of the number of positive nodes.