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Abstract Background To describe our experience with outpatient transperineal biopsy (TPB) without antibiotics compared to transrectal biopsy (TRB) with antibiotics and bowel preparation. The literature elicits comparable cancer detection, time, and cost between the two. As antibiotic resistance increases, antimicrobial stewardship is imperative. Methods In our retrospective review, we compared the TPB to TRB in our institution for outpatient prostate biopsies with local anesthesia from June 1st, 2017 to June 1st, 2019. Patients had negative urinalysis on day of procedure. Patients presenting with symptoms concerning for UTI followed by positive urine culture were determined to have a UTI. Results Two hundred twenty-two patients met inclusion criteria. Age, race, BMI, pre-procedure PSA, history of UTI, BPH or other GU history were similar between both groups. Two TPB patients (1.8%) had post-procedure UTI; one received oral antibiotics and one received a dose of intravenous and subsequent oral antibiotics. There were no sepsis events or admissions. Six TRB patients (5.4%) had post-procedure UTI; five received oral antibiotics, and one received intravenous antibiotics and required admission for sepsis. One TPB patient (0.9%) had post-procedure retention and required catheterization, while four TRB patients (3.6%) had retention requiring catheterization. No significant difference noted in cancer detection between the two groups. Conclusion Outpatient TPB without antibiotic prophylaxis/bowel prep is comparable to TRB in regard to safety and cancer detection. TPB without antibiotics had a lower infection and retention rate than TRB with antibiotics. Efforts to reduce antibiotic resistance should be implemented into daily practice. Future multi-institutional studies can provide further evidence for guideline changes.