OBJECTIVE To evaluate biologic behaviors of unilateral cancers compared with bilateral cancers on prostate-specific antigen (PSA) recurrence after radical prostatectomy. METHODS Analysis included demographic, clinical, and pathologic parameters of 1184 men who underwent RP for clinically localized prostate cancer at our institution between 2002 and 2006. Final pathologic assessment was performed with particular attention to laterality and percentage of tumor involvement, along with other routine parameters. On the basis of percentage of tumor involvement, all cancer foci were ranked as 5% or less, 5.01% to 10%, 10.01% to 15%, or greater than 15%. Statistical analysis was performed with univariate and multivariate methods. RESULTS Overall, 19.2% of 1184 patients had completely unilateral cancers. Prostate-specific antigen recurrence was revealed in 164 of 1184 patients (13.9%) at a mean (+/- standard deviation) follow-up of 2.7 +/- 2.4 years. Among men who had recurrence, 26 of 227 (11.5%) had unilateral tumors and 138 of 957 (14.4%) had bilateral disease (P = 0.25). The most common characteristics associated with PSA recurrence of unilateral tumors in the Cox model were diagnostic PSA level, prostate weight, and pathologic Gleason score (P <0.05). CONCLUSIONS Unilateral or bilateral prostate cancer did not predict PSA recurrence in men receiving radical prostatectomy. In contrast, baseline PSA level and pathologic Gleason score strongly predicted PSA recurrence.