Apolipoliprotein E (apoE), a critical targeting protein in lipid homeostasis, has been found to have immunoinflammatory effects on murine models of infection and malnutrition. The effects of apoE in undernourished and Cryptosporidium parvum-infected mice have not been investigated. In order to study the role of apoE in a model of C. parvum infection, we used the following C57BL6J mouse genetic strains: APOE-deficient, wild-type controls, and APOE targeted replacement (TR) mice expressing human APOE genes (E3/3; E4/4). Experimental mice were orally infected with 10(7)-unexcysted-C. parvum oocysts between post-natal days 34-35 followed by malnutrition induced with a low-protein diet. Mice were euthanized seven days after C. parvum-challenge to investigate ileal morphology, cytokines, and cationic arginine transporter (CAT-1), arginase 1, Toll-like receptor 9 (TLR9), and inducible nitric oxide synthase (iNOS) expression. In addition, we analyzed stool oocyst shedding by qRT-PCR and serum lipids. APOE4/4-TR mice had better weight gains after infection plus malnutrition compared with APOE3/3-TR and wild-type mice. APOE4/4-TR and APOE knockout mice had lower oocyst shedding, however the latter exhibited with villus blunting and higher ileal pro-inflammatory cytokines and iNOS transcripts. APOE4/4-TR mice had increased ileal CAT-1, arginase-1, and TLR9 transcripts relative to APOE knockout. Although with anti-parasitic effects, APOE deficiency exacerbates intestinal inflammatory responses and mucosal damage in undernourished and C. parvum-infected mice. In addition, the human APOE4 gene was found to be protective against the compounded insult of Cryptosporidium infection plus malnutrition, thus extending our previous findings of the protection against diarrhea in APOE4 children. Altogether our findings suggest that apoE plays a key role in the intestinal restitution and immunoinflammatory responses with Cryptosporidium infection and malnutrition.