Objective: The primary aim was to evaluate the change in the total and free PSA levels after antibiotic and non-steroid anti-inflammatory treatment. The secondary aim was to compare this change among the histological subgroups to assess whether it was discriminating. Methods: 97 consecutive patients with PSA >4 ng/dl and scheduled for prostate biopsy were included in this prospective study. 65 patients (group 1) were then put on medical treatment of ciprofloxacin 500 mg bid and diclofenac sodium 75 mg during the routine waiting period before the 2- to 3-week procedure. Randomly selected (every third case) 32 patients (group 2) did not receive this treatment. Free and total PSA tests were repeated before the procedure. The change in the PSA values was compared between the groups and among the histological subgroups in group 1. Results: While in group 1 the decrease in PSA was significant (p = 0.000), this was not the case in group 2. The difference in free PSA values was unremarkable for both groups. In histologically determined cancer cases of group 1, the difference between pre- and post-procedure PSA level was not of note, while in BPH and prostatitis cases it was significant. Conclusion: In cases with increased PSA, medical treatment for a likely subclinical prostatitis resulted in a decrease of PSA, which was significant only in benign conditions.