Introduction Prostate cancer is the most common visceral neoplasm in men and the second one in the United States with the highest mortality behind lung cancer and ahead of colorectal cancer. While prostate cancer mortality rates have been reduced in the United States, Austria, United Kingdom and France, 5-year survival rates have been incremented in Sweden, probably due to a higher diagnostic activity and non-lethal tumor detection. TRPB usually has low rates of serious complications, with a not negligible number of minor complications. Mortality directly associated with this procedure is low and usually related to septic shock. The main complications derived from prostate biopsy can be infectious (mild or severe) and non-infectious (hematuria consistent with hemorrhage, urethral bleeding, rectal bleeding or hemospermia, acute urinary retention, pain or vasovagal reactions). Material and method The objective of the study is to compare three usual TRPB protocols and their relationship with the incidence of complications. Retrospective multicenter observational study conducted in three countries (Spain, Italy and Portugal). We have reviewed the medical records of 3350 men who underwent TRPB to evaluate the existence of prostate cancer, with a minimum evolutionary control of 6 months. Results The mean age was 65,50 years, median 66, range 43–79. The subgroup analysis showed that younger patients had higher rates of acute urine retention (AUR) (p = .0000001). Likewise, our results revealed that younger patients presented more procedural pain (p = .0000001) than older patients. Regarding PSA, the mean value was 10.44, SD 7.73, median 8.15, range 0.98–68.09. A higher body mass index (BMI) was not associated with further infection (p = .000004). When performing the multivariate analysis, it was found that the significant variables in the general group were: age (p = .0013), PSA (p = .0402), local infiltration anesthesia (p = .0001) and prophylaxis with metronidazole + tobramycin + amoxicillin/clavulanic acid + gentamicin (p = .0001), presenting a normal distribution with high confidence interval (95%) and significant correlation. Prophylaxis is the most significant variable for no complications and pain (p = .0001), age (p = .0013) and prophylaxis (p = .0001) are for bleeding, age (p = .0013), prophylaxis and PSA (p = .0001) are for infection, and finally, age (p = .0013), anesthesia with local infiltration and prophylaxis (p = .0001) and PSA (p = .0402) are for AUR. Conclusions Sedation has fewer side effects and complications related to the transrectal prostate biopsy procedure with respect to transrectal local anesthesia. The choice of the antibiotic prophylaxis scheme is decisive in the onset of complications arising from the performance of a transrectal prostate biopsy.