Noncancerous conditions (e.g., benign prostatic hyperplasia and prostatitis) can elevate serum prostate-specific antigen (PSA) levels, limiting the specificity of PSA screening for prostate cancer. In recent years, several studies have also demonstrated a relationship between chronic prostatitis/chronic pelvic pain syndrome and increased PSA levels. However, in asymptomatic patients, routine screening for this diagnosis is not performed before transrectal biopsy to rule out prostate cancer. These asymptomatic men with elevated PSA levels frequently show evidence of inflammation when their expressed prostatic secretions are examined, or on their prostate biopsy specimens. This raises the problem of appropriate evaluation in the presence of chronic prostatitis and elevated PSA levels not only in prostate cancer screening programs, but also in cancer-negative biopsy findings. Thus, there has been investigation into ways to decrease the confounding from inflammation, including repeat PSA measurements after a period of observation or a course of empiric antibiotics. This article reviews the evidence regarding elevations in PSA due to prostatitis and describes the controversy over the optimal approach to reduce its confounding impact on prostate cancer screening. Nowadays, it appears that in patients with prostatic inflammation and increased PSA, an antimicrobial regimen may provide more acceptable initial treatment than proceeding directly to prostate biopsy. Additional evidence is necessary in the form of a randomized clinical trial in which all patients undergo biopsy, regardless of the PSA response to antibiotic or placebo.