The human cathelicidin antimicrobial peptide LL-37 is involved in various aspects of skin biology, including protection against infection, wound healing, and also in psoriasis. The tight regulation of apoptosis is critical in tissue repair and its deregulation is a part of the psoriasis phenotype. Despite being involved in cell death of several cell types, virtually nothing is known about the function of LL-37 in keratinocyte apoptosis. Here we report that LL-37 peptide protects primary human keratinocytes and HaCaT cells from apoptosis induced by the topoisomerase I inhibitor camptothecin (CAM). In particular, pretreatment with LL-37 significantly decreased caspase-3 activity after CAM-treatment. Expression profiling of keratinocytes treated with LL-37 identified the upregulation of cyclooxygenase-2 (COX-2) expression, a gene implicated in protection from apoptosis. In addition to inducing COX-2 expression, LL-37 stimulated the production of its product, prostaglandin E-2 (PGE-2). Moreover, LL-37 induced the expression of inhibitor of apoptosis-2 (IAP-2), implicated in the COX-2/PGE-2 antiapoptotic pathway. Pretreatment with a selective COX-2 inhibitor abolished the antiapoptotic effect of LL-37 and reduced IAP-2 expression implicating that the antiapoptotic effect of LL-37 in keratinocytes is mediated by a COX-2-dependent mechanism involving IAP-2. Thus, overexpression of LL-37 may contribute to reduced keratinocyte apoptosis in conditions such as psoriasis.