Expression of the cytokine-inducible Src homology 2 (CIS) protein and suppressors of cytokine signaling (SOCS) proteins represents an important element of host cell reactions in response to infection. We have demonstrated previously that Cryptosporidium parvum infection down-regulates microRNA-98 (miR-98) and let-7 to induce CIS expression in biliary epithelial cells. We report here that down-regulation of miR-98 and let-7 also coordinates epithelial expression of SOCS4 after C. parvum infection. Targeting of the SOCS4 3' untranslated region by miR-98 or let-7 resulted in translational repression. Functional manipulation of miR-98 caused reciprocal alterations in SOCS4 protein expression. Transfection of miR-98 precursor abolished C. parvum-stimulated SOCS4 up-regulation. Moreover, expression of SOCS4 in epithelial cells showed an inhibitory effect on phosphorylation of signal transducers and activators of transcription proteins induced by C. parvum. These data suggest that miRNAs play an important role in the coordinated regulation of CIS and SOCS expression in epithelial cells in response to C. parvum infection.