Background: Trans-rectal prostate biopsy is commonly used for the diagnosis of prostate cancer; this procedure is associated with infective complications like acute bacterial prostatitis. There is evidence that antibiotic prophylaxis decreases infective events after trans-rectal prostate biopsy, but different regimens are used. Aim: The purpose of the current study is to compare the effect of oral Ciprofloxacin and intravenous (IV) Ciprofloxacin in the prevention of acute bacterial prostatitis during ultrasound-guided transrectal prostate biopsy. Methods: In the current prospective, open-label, randomized, controlled trial, a total of 307 patients with indications for transrectal prostate biopsy were randomized into two groups. These patients received either oral or IV ciprofloxacin before a transrectal needle biopsy of the prostate. All patients underwent ultrasound-guided transrectal prostate biopsy. 3 days after the biopsy, infectious complications including acute bacterial prostatitis were compared between the two groups. Results: 132 IV ciprofloxacin patients and 137 Oral ciprofloxacin patients have participated in the final analysis. Comparing the two groups, demographic and medical baseline data was similar (P<0.05). The rate of acute bacterial prostatitis in IV and Oral patients was 5.3 % (7/132) and 21.16 % (29/137), respectively (P=0.0001). Also in both groups, all infected patients had bacteriuria, Pyuria, Hematuria, Leukocytosis, fever, and Lower urinary tract symptoms. Conclusions: Single-dose IV ciprofloxacin significantly reduced acute bacterial prostatitis after biopsy compared with oral ciprofloxacin in patients undergoing transrectal prostatic biopsy. Further study of these observed findings with larger patient numbers is indicated.