Apolipoprotein E (apoE) is a multifunctional protein known for its roles in lipid metabolism and immune regulation. This chapter explores the immunomodulatory effects of apoE on colitis, with a focus on inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD). apoE exists in three major isoforms—apoE2, apoE3, and apoE4—each with distinct impacts on inflammation and immune responses. The APOE2 and APOE4 alleles are associated with increased risk and altered disease outcomes in IBD, while the APOE3 allele offers protective effects. This part delves into apoE’s interactions with gut-associated lymphoid tissues, cytokine production, and macrophage polarization, highlighting its influence on gut immunity and intestinal barrier function. Furthermore, the role of apoE in shaping the gut microbiota and its potential therapeutic implications are discussed. This synthesis of current knowledge underscores the importance of genetic factors in IBD pathogenesis and progression, pointing to genotype-based personalized therapies as a promising avenue for managing colitis.