Milk fat globule membrane surrounds the fat droplets of milk. It is a biopolymer containing primarily membrane glycoproteins and polar lipids which contribute to its properties as a possible neutraceutical. The aims of the studies were to determine if dietary milk fat globule membrane: (1) confers protection against colon carcinogenesis; and (2) promotes gut mucosal integrity while decreasing inflammation compared to diets containing corn oil or anhydrous milk fat. Aim 1. Three dietary treatments differing only in the fat source were formulated: (1) AIN-76A, corn oil; (2) AIN-76A, anhydrous milk fat; and (3) AIN-76A, 50% milk fat globule membrane, 50% anhydrous milk fat. Each diet was formulated to contain 50 g/kg diet of fat and to be identical in macro and micro nutrient content. To assess protection against colon carcinogenesis, male, weanling Fischer-344 rats were randomly assigned to one of the three dietary treatments. Animals were injected with 1,2-dimethylhydrazine once per week at weeks 3 and 4. After 13 weeks animals were sacrificed, colons were removed, and aberrant crypt foci were counted by microscopy. Rats fed the milk fat globule membrane diet (n = 16) had significantly fewer aberrant crypt foci (20.9 ± 5.7) compared to rats fed corn oil (n = 17) or anhydrous milk fat (n = 16) diets (31.3 ± 9.5 and 29.8 ± 11.4 respectively; P < 0.05). Aim 2. Male BALB/c mice were randomly assigned to one of two diets: AIN- 76A, corn oil or AIN-76A, 50% milk fat globule membrane, 50% anhydrous milk fat. After 5 weeks mice were injected with saline vehicle control or lipopolysaccharide and gavaged with dextran-FITC. To assess gut mucosal integrity and inflammation, serum samples were assayed for dextran-FITC 24 and 48 hours after gavage, and a panel of 16 cytokine concentrations was analyzed. Serum concentrations of IL-6, IL-10, IL-17, MCP-1, IFNγ, and TNFα decreased and gut permeability decreased 45% in lipopolysaccharide challenged mice fed milk fat globule membrane diet compared to control diet at 24 hours (P < 0.05). Overall, the results of these aims suggest that diets containing milk fat globule membrane are protective against colon carcinogenesis, inhibit the inflammatory response, and protect against gastrointestinal stress.