<i>Introduction:</i> To identify risk factors for biochemical failure after radical prostatectomy (RP) in men with pathologically organ-confined (OC) prostate cancer (PCa). <i>Materials and Methods:</i> Clinical and pathological features of 350 consecutive patients with pathologically OC PCa treated only with RP and bilateral pelvic lymphadenectomy were analyzed, retrospectively, to identify predictor parameters of prostate-specific antigen (PSA) failure (PSA ≧0.4 ng/ml). The median follow-up was 58.6 months (range: 3.9–183 months). All pathological specimens were step sectioned at 4-mm intervals. Kaplan-Meier progression-free survival rates and χ² test were adopted for statistical analyses. Multivariate Cox proportional hazard regression models were used to test the association between pathological Gleason score and surgical margin status. <i>Results:</i> 67 patients (19.1%) failed at a median follow-up of 40.2 months (range 1.9–123.3). Age and preoperative PSA failed to reveal significance also in patients with serum PSA ≧20 ng/ml (p = 0.46). Patients with T3 clinical stage had a higher progression rate compared to T1C and T2 (43.5 vs. 27.8 and 17.3%, respectively) even if no high statistical significance was pointed out. Presence of perineural infiltration (p = 0.04) and prostatic apex infiltration (p = 0.74) in the prostatectomy specimens failed to reveal significance. A high pathological Gleason score (≧7; p = 0.0003) and surgical margin status (p < 0.0001) were shown to be the most powerful predictive parameters of biochemical progression. <i>Conclusions:</i> In patients with pathologically OC PCa the presence of a high pathological Gleason score and positive surgical margins appear to represent the most important factors for prediction of outcome following RP.