In some regions of the world, co-existence of schistosomiasis and hepatitis C (HCV) infection is common. Because the morbidity in human schistosomiasis is primarily due to host cell-mediated immune response, it was of interest to determine the effects on Schistosoma mansoni infection of an immune stimulator used in the standard treatment of HCV infection. Schistosoma mansoni-infected mice were treated with PEG-interferon-α-2a (PEG-IFN-α) by subcutaneous injection. Groups 1, 2, and 3 received 0.2 µg, 0.6 µg, and 1 µg PEG-IFN-α/wk, respectively, while group 4 received saline. The total worm burden was lower in all treated groups, with a maximal reduction of 35% after 9 wk of treatment with 1 µg PEG-IFN-α. Interferon treatment also increased the proportion of single worms over pairs. Ova counts in intestine and liver, as well as the number of liver granulomas, were greatly decreased at all time points for all treated groups. PEG-IFN-α also had inhibitory effects on the size of granulomas after 4 wk of treatment. The results suggest that PEG-IFN-α may be worth investigating for the treatment of human schistosomiasis when standard oral agents cannot be used, or when rapid inhibition of granuloma formation may be a priority.