We assessed whether the quantification of cancer invasion into the perineural space influences the prognosis of patients treated with radical prostatectomy. We conducted a retrospective study of clinical and pathologic features in 640 consecutive patients with clinical stage Tla-T3bNXM0 prostate cancer who were treated with radical retropubic prostatectomy by the same surgeon between 1989 and 1995. None had received preoperative hormonal therapy or radiotherapy. Detailed pathologic analysis, including the presence and maximum diameter of perineural invasion (PNI), was performed by 2 pathologists. Treatment failure was defined as either a serum prostate-specific antigen (PSA) level > 0.4 ng/mL and rising or initiation of adjuvant therapy. The median follow-up time was 48 months (range, 1 to 111 months). Overall, PNI was detected in 477 patients (75%). The progression-free 5-year probability rate after prostatectomy for patients with PNI was 70% +/- 3% compared with 94% +/- 2% for patients without PNI (P <.001). The mere presence of PNI was not an independent predictor of progression in a Cox proportional hazards analysis when the other established prognostic factors (serum PSA level, pathologic stage, surgical margin, and tumor volume) were considered. However, the increasing diameter of the largest focus of PNI was strongly associated with other established prognostic factors and the probability of progression after radical prostatectomy. Although little adverse effect in patients with PNI < 0.25 mm was seen 5 years after surgery, those with a PNI diameter of 0.25 to 0.5 mm were significantly (P <.001) less likely to remain free of progression; only 36% of those with PNI of 0.5 to 0.75 mm (P <.001) and 14% of those with PNI > or =0.75 mm (P =.002) were free of progression. In a Cox proportional hazard analysis, the PNI diameter was an independent predictor of prognosis. These results support that the measurement of the PNI diameter, easily recorded from prostatectomy specimens, could add important information to the prognosis of prostate cancer patients. Controversy regarding the significance of PNI may result from the lack of quantitative assessment of PNI in previous studies.