ABSTRACTMixed parasitic infections could affect the host immunological responses and re-design the pathogenesis of each other. The impact of Toxoplasma gondii(T. gondii) and Trichinella spiralis(T. spiralis) co-infection on the immune response remains unclear. The objective of the present study was to investigate the possible effect of chronic trichinellosis on the immune response of rats infected with T. gondiivirulent RH strain. Animals were divided into four groups: group I: non-infected negative control; group II: infected with T. spiralis; group III: infected with T. gondiiand group IV: infected with T. spiralisthen infected with T. gondii35 days post T. spiralisinfection (co-infected group). The interaction between T. spiralisand T. gondiiwas evaluated by histopathological examination of liver and brain tissues, immunohistochemical expression of inducible nitric oxide synthase (iNOS), and β-catenin in the brain tissues, and CD4+and CD8+T cells percentages, and tumor necrosis factor (TNF)-alpha expression in the spleen tissues. Along with, splenic interleukin (IL)-4 and IL-10 mRNA expression levels were measured 15 days post-Toxoplasmainfection. Our study revealed that prior infection with T. spiralisleads to attenuation of Th1 response against T. gondii, including iNOS, TNF-α, and CD8+T-cell response with improvement of the histopathological changes in the tissues. In conclusion, in the co-infected rats, a balanced immune response has been developed with the end result, improvement of the histopathological changes in the liver and brain.