Interferon (IFN)-&ggr; and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) enhance tumor immunogenicity. The authors assessed tolerability and effectiveness of a combination therapy of these recombinant human (rh) cytokines in patients with inoperable hepatocellular carcinoma (HCC). In a monocentric, open, nonrandomized pilot study, rhGM-CSF (5 &mgr;g/kg qd, Monday and Tuesday) and rhIFN-&ggr; (100 &mgr;g qd, Wednesday and Thursday) were subcutaneously administered in 9-week cycles. Primary objective was survival, as secondary outcomes volumetric changes of tumor mass and biologic parameters reflecting systemic immunologic or local tumor responses were measured. Only patients with complete response (CR), partial response (PR), or stable disease (SD) proceeded to new treatment cycles. Fifteen patients (median 63 years, range 46–74 years, all men) were enrolled. Survival after the first cycle was 80% with SD in 9 of 15 patients (60%). PR was detected in one patient after the second cycle. Two patients finished five treatment cycles. Overall survival at 26 and 52 weeks was 40% and 20%, respectively. Median survival in patients with inducible HLA-DR on hepatoma cells (40%) was increased (42 weeks, 27–100) as compared with HLA-DR negative cases (60%; 13 weeks, 8–23; p < 0.0001), and a control group (p = 0.01). Parameters reflecting systemic immunomodulatory activities were not associated with clinical outcome. In 13 of 15 patients (87%), adverse events were reported, all less than grade 2 and none requiring therapy discontinuation. Immunotherapeutic approaches hold promise to prolong survival in selected patients with advanced HCC who respond by enhanced tumor immunogenicity.