PurposeTo assess the impact of zonal origin on positive bladder neck (BN) margins and prostate-specific antigen (PSA) failure or early adjuvant therapy in the patients with complete long-term follow-up after radical prostatectomy (RP).MethodsA set of 4512 men were identified who underwent RP in Western Australia (WA) from March 2000 to December 2016 and had complete long-term follow-up. Thet-test, Pearson chi-square test and Kaplan–Meier method with the log-rank test were used to evaluate differences between the transition zone (TZ) and peripheral/central zone (PZ/CZ) cancer. Univariate and multivariable Cox proportional hazard regression models were applied to assess parameters on PSA failure and early treatment.ResultsThe positive BN margin rate for TZ cancer fell significantly over the study period. However, BN margin rates increased for PZ/CZ cancer over the time. Data of 4512 patients with median follow-up of 9.1 years confirmed that the high-risk TZ tumours with negative margins had a significant lower rate of PSA failure or early treatment compared to those high-risk PZ/CZ tumours with negative margins.ConclusionProstate cancer zonal origin significantly impacts long-term biochemical outcomes in high-risk and margin-negative patients. BN invasion with margin involvement is more frequent in the TZ cancer and can be reduced by pre-operative identification of cancer zonal origin and adjustment of surgical procedures.