Abstract Objectives To compare pain control results between periprostatic nerve block alone and combined with topical prilocaine-lidocaine cream as local anesthesia of prostate biopsy. Methods Three hundred patients were randomized to receive PNB (group 1), topical anesthesia of the anal ring, anal canal, and anterior rectal wall combined with PNB (group 2) and placebo (group 3). Patients were asked to use scale of 0–10 to complete a visual analogue scale questionnaire about pain during probe insertion (VAS1), periprostatic infiltration (VAS2), and cores (VAS3). Results Pain during probe insertion in group 2 was significantly less than in groups 1 and 3 (VAS1, 0.29 vs. 1.46 and 1.48; p < 0.0001). Pain during periprostatic infiltration was also reduced in group 2 compared with group 1 (VAS2, 1.06 vs. 2.39; p < 0.0001). Pain control was similar during biopsy in the PNB and combined groups (VAS3, 0.43 vs. 0.37; p = 0.77) and was superior to group 3 (VAS3, 3.02; p < 0.0001). In younger patients (cut off, median age 67 yr) these differences were still significant between groups 1 and 2 (VAS1, 1.95 vs.0.31; p < 0.0001 and VAS2, 2.97 vs. 1,15; p < 0.0001), but not in older patients (VAS1, 0.91 vs. 0.28; p = 0.06; VAS2, 1.52 vs. 0,92; p = 0.06). Vagal symptoms were registered in 36 (12%) patients in all groups. Sepsis occurred in one group 1 patient and in one group 2 patient. Rectal bleeding was observed in one group 2 patient. Conclusion Combined prilocaine-lidocaine cream topically placed with PNB is superior to PNB alone and may be of maximum benefit for younger patients.