Background: Schistosomiasis is an important cause of hepatic fibrosis in man. As etiological therapy alone is not enough to treat hepatic fibrosis, finding other strategies that can control the disease is important. Considering the dominant role of vaccination, research on gamma radiation-attenuated vaccine has become a new focus and has very promising value. Aim of the work: The objective of this study was to detect the effect of vaccination with attenuating dose of gamma radiation of schistosomules in controlling immunohistochemical changes in mice model of human schistosomiasis mansoni.  Materials and methods: Forty mice were divided into four groups (ten each). Group A served as normal control, group B was infected by subcutaneous (S. C.) injection with 100 S. mansoni cercariae/mouse (infected control), group C was vaccinated by (S.C.) injection with 500 schistosomulae irradiated with 20 Krad gamma-radiation (vaccine control) and group D was vaccinated by (S.C.) injection with the same dose of irradiated schistosomules and then challenged after 4 weeks by S.C. injection with 100 S. mansoni cercariae. Expression of α-smooth muscle actin (α SMA), desmin, collagen type-1 and transforming growth factor-beta1 (TGF-β1) in the extracellular matrix (ECM) using immunohistochemistry were done. Results: exhibited in infected control group B marked expression of α-SMA, desmin, collagen type-1 and TGF-β1. These changes were moderate in vaccinated-control group C while few changes were detected in vaccinated-challenged group D.         Conclusion:It was concluded that using 20 Krad-gamma irradiated schistosomules as vaccine is effective in controlling liver pathology and reduces immunohistochemical changes.