Lactoferrin (Lf) functions in the orchestration of iron homeostasis, immune maturation, and proliferation of intestinal epithelial cells (IEC) in the breastfed infant. The exaggerated inflammatory response of enteropathogenic‐derived infantile diarrheas is potentiated, in part, by exposure to lipopolysaccharide (LPS). Lf sequesters the lipid A moiety of LPS with high affinity and may dampen the effects of overt TLR complex activation. In the present study, effects of Lf in the presence of LPS on the expression patterns of stress‐response genes were examined using a fetal IEC model. FHs74 cells were treated for 24 h with 400 μg/ml native (N)‐ and holo (H)‐ human (hLf), bovine (bLf), or commercially available bovine Lf (cbLf) with or without 1 μg/ml LPS. Cell viability was attenuated (> 30%) by LPS challenge, an effect that was ameliorated by the addition of Lf(s). Using PCR array profiling N‐hLf treatment was determined to differentially modulate LPS‐induced up‐regulation of numerous intermediates and products of the NFκB, MAPK, and Fas signaling pathways. Q‐PCR was employed to validate PCR array findings that Lf(s) mediates perturbations of multiple pro‐inflammatory cytokines due to LPS challenge including IL1, IL6, and IL8. Our findings suggest Lf may protect the neonatal intestinal epithelium against LPS by altering the expression of key regulatory genes associated with an LPS derived inflammatory response.Grant Funding Source: N/A