Introduction: The aim of this study was to determine if antibiotic or anti-inflammatory medications lower serum prostate-specific antigen (PSA) in the presence or absence of inflammation in the prostatic secretions of patients with PSA levels between 2.5 and 10 ng/ml and normal digital rectal examinations (DRE). Materials and Methods: Patients with PSA levels between 2.5 and 10 ng/ml and normal DRE were candidates for the study. One hundred and eight patients with positive expressed prostate secretion (EPS) were randomized into antibiotics, anti-inflammatory and control groups (groups 1, 2 and 3, respectively), and 108 patients with negative EPS were randomized into similar groups (groups 4, 5 and 6, respectively). Repeat PSA levels of all patients were obtained 6 weeks after randomization and 10 core prostate biopsies were performed. Results: Median PSA levels in group 1 before and after treatment were 5.2 (4.3-6.4) and 4.0 ng/ml (3.1-4.9), respectively (p < 0.001). The only significant decrease in PSA was observed in group 1. The percent change in PSA levels in group 1 was significantly greater than both in its control group (group 3; p < 0.001) and the EPS- antibiotics group (group 4; p < 0.001). Conclusions: Antibiotherapy significantly reduces serum PSA only in EPS+ patients, which justifies limiting the use of prebiopsy antibiotics to EPS+ patients with a normal DRE and PSA level between 2.5 and 10 ng/ml, minimizing the major drawbacks of empirical antibiotics usage. Copyright © 2010 S. Karger AG.