Abstract Introduction/Objective: Introduction Intraoperative frozen-section analysis allows real-time histologic assessment of surgical margins (SMs) and identification of candidates for nerve-sparing (NS) procedures in radical prostatectomy (RP). Objective: To examine the efficacy of a systematic neurovascular structure-adjacent frozen-section examination (NeuroSAFE) during open and robotic assisted radical prostatectomy (RARP). Methods/Case Report From January 2019 to December 2020, 486 consecutive RPs were performed at the academic hospital Fuerth. Of these, 289 (59 %) were conducted with NeuroSAFE. Surgical procedure: NeuroSAFE included the whole laterorectal circumference of the prostate corresponding to the neurovascular bundle to determine the SM status. Outcome measurements and statistical analysis: The impact of NeuroSAFE on NS frequency and SM status was analyzed by chi-square test in matched cohorts. Data obtained from 289 RPs performed with NeuroSAFE were compaired to those from 197 RP without NeuroSAFE. Results (if a Case Study enter NA) In NeuroSAFE RPs, frequency of NS was significantly higher in lower pT stages (pT2 and pT3a: 78 % vs 68%, 58% vs 51%, p < 0.0001, p = 0.047, respectively), whereas in stage ≥ pT3b, there was no significant difference in NS rate (53% vs 34%; p = 0.14). PSM rates were significantly lower only in pT2 tumors (all stages: 35% vs 24%, p=0.06; pT2: 12% vs 15%; p=0.02; pT3a: 36% vs 35%; p=0.6 and ≥pT3b: 39% vs 52%, p=0.3) compared with the matched non-NeuroSAFE RPs. Positive SMs (PSMs) were leading to a secondary resection of the ipsilateral neurovascular tissue. Secondary wide resection resulted in conversion to a definitive negative SM (NSM) status in 85 % of the patients. Conclusion NeuroSAFE enables real-time histologic monitoring and oncologic safety of a NS procedure. Systematic NeuroSAFE significantly increases NS frequencies and reduces PSMs in stage pT2 tumors. Patients with a NeuroSAFE-detected PSM could be converted to a prognostically more favorable NSM status by secondary wide resection.