The growth of hepatocellular carcinoma (HCC) is thought to be dependent on androgens, as androgen receptors are present in most of these tumors. The aim of this multicenter trial was to assess the effect of antiandrogens in patients who have advanced HCC. Male patients with advanced HCC were randomized into 2 groups treated with (1) leuprorelin (3.75 mg/mo subcutaneously), flutamide (750 mg/d orally), and tamoxifen (30 mg/d orally) or (2) tamoxifen alone (30 mg/d orally) administered until death. Survival was the main end point (log-rank test). The required sample size was 375 patients (alpha, 5%; beta, 10%; 1-year survival, 45% in treated group and 30% in controls). Between February 1994 and January 1998, 376 male patients (mean age, 66 years; treated group, n = 192; control group, n = 184) were included. No baseline imbalance was found between the groups. At the reference date (January 1, 2003), 183 deaths (95.3%) were observed in the treated group and 177 deaths (96.2%) were observed in controls. Thirteen patients were lost to follow-up. Median survival time was estimated to be 135.5 days (95% CI, 112-189) and 176 days (95% CI, 141-227) in treated and control groups, respectively (P = .21). Crude and adjusted relative risks of death in the treated group were estimated at 1.14 (95% CI, 0.93-1.40) and 1.08 (95% CI, 0.87-1.33; P = .48) respectively. Premature interruption of treatment was more frequent in the treated group (n = 45) than in controls (n = 22; P = .0045), mainly because of digestive side effects. In conclusion, no benefit in survival was found with antiandrogenic treatment in male patients with advanced HCC.