This article reports a prospective randomized controlled study to investigate the effect of sex hormone therapy combined with intra-arterial chemotherapy for hepatocellular carcinoma (HCC). Thirty patients with unresectable HCC were randomly divided into two groups. A catheter was inserted into the hepatic artery of all patients. The first group (group A) was administered 60 mg/m2 of cisplatin (CDDP) on day 15 and 13 mg/m2 of Adriamycin (ADM) on day 1 and 8 postoperatively via the hepatic artery cannula; in addition, a daily dose of 150 mg 5-fluorouracil (5-FU) was administered orally. Tamoxifen (TAM) 25 mg/m2 daily and medroxyprogesterone acetate (MPA) 400 mg/m2 daily were also administered orally. TAM and MPA administration were alternated every 4 weeks. For the second group (group B) the same protocol of anticancer drugs administration, without the hormonal agents, was given. At least three courses of the treatments were carried out. Twelve patients in group A and 14 in group B were evaluated. Partial response of the hepatic tumor to the treatments was observed in 33.3% of group A patients and 21.4% of group B patients, a difference that was not statistically significant. The 1-year survival rate was 44.5% in group A and 33.0% in group B. The performance status of 25% of the patients in group A was significantly improved compared with 14.3% in group B (p < 0.05). TAM- and MPA-combined chemotherapy may not prolong the survival of patients with HCC, although it improves their quality of life.