Hypoxia induces survival signals in hepatocellular carcinoma (HCC). Hypoxia and retinoic acid (RA) may also induce interleukin-2 (IL-2) receptor expression, and thus we evaluated if RA and IL-2 receptor-targeted therapy are indicated in hypoxic HCCs. RA induced IL-2 receptor expression (R alpha, R beta, R gamma) in HCC cells, whereas hypoxia specifically induced IL-2 R gamma expression. IL-2 stimulated hypoxic HCC cell growth via p42/44 MAPK activation. Combination of denileukin diftitox and RA significantly suppressed hypoxic HCC cell growth compared to single agent-treated or normoxic cells. Therefore, denileukin diftitox and RA may be therapeutically implicated in infiltrative HCCs which are exposed to hypoxic environments.