Giardiasis is one of the most frequent entero-parasites worldwide; its prevalence is more common in developing countries. Giardia lamblia is considered one of the opportunistic parasites and its clinical manifestations represent the expression of host resistance and parasite virulence. As of chronic giardiasis cases were expected to worsen in immunosuppressed patients with development of various complications. This work assessed the histolopathological and the possible immunological effects of infection with G. lamblia in an immunosuppressed experimental animal model in comparison to immunocompetent one. Mice were divided into 4 groups: group I: immunocompetent (IC) mice infected with G. lamblia cysts, group II: immunosuppressed (IS) mice infected with cysts, group III: uninfected immunocompetent mice and group IV: uninfected immunosuppressed mice. From each group, small intestine was removed for histopathological and molecular studies. Also, cyst counting in the stool of infected mice was estimated. We found that the number of G. lamblia cysts in the stool of IS mice was significantly higher than that from IC ones. Shortening of the villi was more pronounced in the IS than in IC group. Furthermore, intraepithelial lymphocytic count, goblet cell count and mast cell count were significantly decreased in the IS infected group as compared to IC ones. Expression of interleukin- 6 mRNA showed high expression in IC infected mice while it was weak in IS mice. In conclusion, the present study revealed the importance of the innate immunity presented by goblet cells, mast cells and other adaptive immunity responses; in the clearance of Giardia.