Patients coinfected with hepatitis C virus (HCV) and the trematode, Schistosoma mansoni, have an increased incidence of viral persistence and accelerated fibrosis. To investigate immunological mechanisms responsible for this more aggressive natural history of HCV, the core HCV-specific T-cell responses were analysed in 44 donated blood units rejected because they had antibodies to HCV (anti-HCV). Half also had anti-S. mansoni antibodies, evidence of past or active infection. HCV-specific ELISPOT responses were examined using pools of 180 overlapping 9-mer peptides with offsets of one covering the core of HCV genotype 4a. Comparison of T-cell responses in blood units positive for both anti-HCV and anti-Schistosoma antibodies with blood units positive only for anti-HCV antibodies showed a significant decrease in core-specific T-cell IFN-γ (505± 46 vs. 803 ± 66 ISC/106 cells, P < 0·001), IL-4 (2 ± 108 vs. 641 ± 131 ISC/106 cells, P < 0·001), and IL-10 (159 ± 105 vs. 466 ± 407 ISC/106 cells, P < 0·002) responses. In contrast, there was no significant difference in cell-mediated immune response (CMI) to PHA mitogen between these two groups. Therefore, we concluded T cells from persons with anti-Schistosoma have reduced IFN-γ, IL-4, and IL-10 secreting HCV-specific T-cell responses. This may explain why Schistosoma coinfection increases persistence and severity of HCV infection.