A retrospective study was performed to evaluate how the prostate-specific antigen (PSA) response to testosterone replacement therapy (TRT) varies with age, mode of testosterone treatment, and baseline levels of PSA and testosterone. In total, 48 consecutive hypogonadal men who completed 1 year of TRT were evaluated. All men had a negative prostate biopsy obtained prior to initiating TRT. Men received TRT in the form of intramuscular injections (n = 33) or topical gel (n = 25) based on clinical response. Comparisons in the change in PSA after 1 year of TRT were made based on various thresholds for age and baseline values of PSA, total testosterone (TT), and free testosterone (FT). Baseline levels of TT (297.7+/-156.6 vs 292.7+/-89.7 ng/dl; P = 0.88) and FT (0.95+/-0.3 vs 1.1+/-0.3 ng/dl; P = 0.08) were similar for the injection and transdermal groups, and both groups also had similar baseline PSA values (1.92+/-1.9 vs 1.71+/-1.9 ng/ml, respectively; P = 0.67). After 1 year of TRT, mean PSA values did not differ significantly between groups, nor did the mean increase in PSA (P > 0.05). The overall mean increase in PSA was 0.31+/-0.76 ng/ml. After one year of TRT, PSA was decreased in 21%, unchanged in 22%, and increased in 57%. Only 24% of the entire group demonstrated a PSA increase of 0.5 ng/ml or greater. No statistical difference was found in the change in PSA based on patient age, baseline PSA levels, or baseline levels of TT or FT. TRT causes only a mild increase in PSA in most hypogonadal men, and does not appear to be influenced by the mode of TRT, age, or baseline levels of PSA or testosterone.