Interferon- (IFN-)alpha is currently the standard of care treatment for patients with chronic hepatitis C virus (HCV) infection. A significant part of the benefit of IFN-alpha in chronic hepatitis C is believed to be related to the activation of lymphocytes such as T cells and natural killer (NK) cells, which participate in the elimination of infected cells. Histamine dihydrochloride (HDC) has been shown to potentiate the IFN-alpha-induced activation of T cells and NK cells by a mechanism that involves the protection of these lymphocytes against oxygen radical-induced functional inhibition and apoptosis. This study was designed to examine the efficacy and safety of HDC in combination with IFN-alpha-2b in treatment-naïve patients with chronic HCV infection. All patients received IFN-alpha-2b, 3 MIU, three times weekly via subcutaneous injection, and were randomized to one of four HDC regimens (1 mg of either: once a day, three times a week; once a day, five times a week; twice a day, three times a week or; twice a day, five times a week). The doses of HDC in combination with IFN-alpha-2b resulted in sustained viral response rates ranging from 31% to 38%. Sustained biochemical response rates ranged from 28% to 41% across the four treatment groups. Patients infected with HCV genotype 1, and those with high baseline viral levels, which are characteristics associated with poor prognosis, had sustained virologic response rates ranging from 18% to 42% and 15% to 39%, respectively. Combination treatment was generally well tolerated. We propose that the potential benefit of HDC + IFN therapy for chronic HCV infection should be the focus of further investigation.