Objective To report the first prospective comparative analysis of robot-assisted (RASP) vs open simple prostatectomy (OSP) for large prostate glands. Materials and Methods We prospectively analysed 41 patients who underwent surgery for benign prostatic hyperplasia between 2014 and 2017 at one of two university institutions. Patients were grouped according to the procedure (OSP or RASP) and matched in terms of age, prostate volume, body mass index and prostate-specific antigen level. The two groups were followed prospectively for 3 months, and their postoperative and functional outcomes were compared. Results Six patients (40%) in the OSP and seven patients (27%) in the RASP arm of the study had preoperative urethral catheters as a result of relapsed urinary retention. The amount of blood loss during surgery was significantly lower in the RASP arm (539 vs 274 mL), but the operating time was significantly longer (134 vs 88 min). One patient in the RASP group experienced a Clavien-Dindo grade II complication, whereas in the OSP group, four patients experienced serious complications (27%); one patient had a bladder rupture (Grade III), one patient developed deep venous thrombosis (Grade II), and two patients required blood transfusions (one unit each; Grade II). Two patients (one from each group) experienced urinary retention after catheter removal that required a urethral catheter replacement. In the follow-up period, there were significant and similar improvements in International Prostate Symptom Scores, uroflowmetry results and post-void residual urine volume in both groups. Conclusion The results showed that RASP provided similar functional outcomes to those of OSP, whilst maintaining a good (or even better) safety profile. Our results suggest that RASP is a viable, efficient and potentially superior alternative to the open procedure.