The role of rectal culture-guided antimicrobial prophylaxis (TAP) in reducing infectious complications (IC) after transrectal-ultrasound prostate biopsy (TRUSPBx) is conflicting. We assessed the prevalence of IC in a cohort of men at high risk for IC submitted to TRUSPBx and treated with either TAP or empirical prophylaxis (EAP). Data from 53 patients at high risk for IC undergoing TRUSPBx were collected. Patients who did not receive a rectal swab (RS) were treated with EAP with fluoroquinolones (FQs). Of those who received the RS, patients with FQ-susceptible organisms received ciprofloxacin while those with FQ-resistant organisms received TAP. Office visits were scheduled to investigate the rate of complication at day 7 and 30 after TRUSPBx. Comorbidities were scored with the Charlson Comorbidity Index (CCI). Descriptive statistics and logistic regression models detailed the association between clinical parameters and IC rate. Out of 53 men, 17 (32.1%) had RS while 36 (67.9%) did not. All RS cultures were positive for E. Coli and 4 (23.5%) reported FQ-resistant pathogens. Considering risk factors for IC, no difference was found in terms of CCI, rate of diabetes, UTIs or recent antibiotic utilization between groups. Overall, 12 (22.6%) men reported IC, with a greater proportion of them belonging to the group treated with EAP (30.6% vs 5.9%; p = 0.045). Of these, 9 (25.0%) patients, all treated with EAP, developed post biopsy UTIs. E. Coli sustained all UTIs and 7 (77.7%) were FQ resistant. At multivariable analysis, CCI≥1, a history of UTIs/prostatitis and recent antibiotic utilization (all p<0.04) were the most powerful predictors for ICs. In conclusion, we found that compared to EAP, TAP significantly reduces ICs, in men at high risk for post TRUSPBx IC. Patients at risk for IC, especially those with recent antibiotic utilization, CCI≥1 and a history of UTIs/prostatitis before biopsy, could benefit from TAP.