Interferon-alpha (IFN-α) has recently been shown to modulate in vitro T helper (Th) 1–driven responses in the peripheral blood mononuclear cells (PBMC) of patients with hepatitis B virus or C virus infection. In this study, we examined the in vitro effects of IFN-α subtypes (IFN-α1, -α2, -α5, -α8, and -α10) on the Th1/Th2 balance in PBMC obtained from patients with hepatitis virus infection–associated liver disorders and chronic hepatitis (CH), in comparison with the effect on healthy control volunteer PBMC. The Th1-type cell percentages and Th1/Th2 ratios were significantly higher in the PBMC of patients when compared with controls both before and after cultivation in vitro, with the IFN-α subtypes. The IFNα-5 induced an increase in the Th2-type cell percentages in both control and patient PBMC, resulting in that IFN-α5 lowered the Th1/Th2 ratio in patients with CH. Furthermore, statistical analysis revealed that IFN-α8 significantly promoted an increase in the Th1/Th2 ratios of PBMC from patients with CH and liver cirrhosis (LC) but not that of PBMC from patients with LC–hepatocellular carcinoma (HCC) and HCC. These findings imply that hepatitis virus infection and its disease status modify the effects of IFN-α subtypes on Th1 and Th2 immune balance in patients. Our findings should help to elucidate the mechanisms underlying successful IFN therapy for hepatitis virus infection and prevention of hepatocellular carcinogenesis.