Defensins are cationic antimicrobial peptides that contribute to regulation of host cell function also. Here, we report on the regulation of cell death by Human Defensin 5, the major antimicrobial peptide of ileal Paneth cells. We find that Human Defensin 5-mediated cellular effects depend on functional expression of Tumor Necrosis Factor receptors and downstream mediators of TNF signaling. Our data indicate the involvement of interactions between Human Defensin 5 and the extra-cellular domain of Tumor Necrosis Factor receptor 1. Human Defensin-5 also induces apoptosis intrinsically by targeting the mitochondrial membrane.