Purpose We evaluated men with documented chronic prostatitis and elevated serum prostate-specific antigen (PSA) to determine whether treatment with antibiotics and anti-inflammatory drugs can lower serum PSA and the cancer detection rate in patients with post-treatment PSA <4 ng/ml. Materials and Methods Eighty-six men who presented with serum PSA greater than 4 ng/ml and who were subsequently diagnosed with chronic prostatitis with greater than 10 white blood cells per high power field in expressed prostatic excretions were included in this prospective study. Patients meeting these criteria underwent treatment with a 4-week course of antibiotics and nonsteroidal anti-inflammatory agents. Follow-up PSA and transrectal ultrasonography-guided prostate biopsy were performed within 2 months of treatment for all patients. Results Mean patient age was 56.2 years (range, 37-72 years). Mean PSA (ng/ml) decreased by 33.8%, from 8.12 (range, 4.02-24.8) to 5.37 (range, 1.35-12.94), after treatment (p=0.001). Pathological studies revealed prostate cancer in 18 cases (20.9%), chronic inflammation in 64 (74.4%), and benign prostatic hypertrophy in 4 (4.7%). The prostate cancer detection rate according to the follow-up PSA level, below 2.5, from 2.5 to 4.0, and above 4.0, was 13.3% (2/15), 13.6% (3/22), and 26.5% (13/49), respectively. Conclusions When chronic prostatitis with elevated PSA is identified, antibiotic and anti-inflammatory treatment can lower these PSA levels. However, the possibility of prostate cancer remains in patients whose PSA level decreases to less than 4 ng/ml, even in those with a PSA level less than 2.5 ng/ml.