We report 5 patients with advanced metastatic prostate cancer who took bicalutamide 50 mg/day for “second-line” hormonal manipulation and demonstrated a rapid rise in prostate-specific antigen (PSA) shortly after the initiation of bicalutamide. After discontinuation of the drug, PSA levels declined in 4 patients and stabilized in the fifth. In 2 of the patients, the PSA rise was associated with an increase in pain level, which subsided after the treatment was stopped. The timing of the rapid changes in PSA and pain levels suggests a direct effect of bicalutamide. The most probable explanation for this observation is a very early agonist activation of androgen receptor by bicalutamide, similar to the underlying mechanism of the “antiandrogen withdrawal syndrome.”