Iron acquisition is an absolute requirement by most microorganisms for host survival. In this work, we investigated the Campylobacter jejuni iron binding Dps protein for a potential role in virulence. In vitro assays using J774A.1 macrophage-like cells demonstrated a 2.5 log reduction in C. jejuni survival of the Dps mutant and a reduction of four logs in invasion of HEp-2 epithelial cells compared to the wild-type strain. To examine the role of the dps gene in host pathogenesis, the piglet model was used in C. jejuni challenge studies. In vivo inoculation studies of newborn piglets with wild-type C. jejuni demonstrated an 11-fold upregulation of the dps gene and intestinal lesion production typical of campylobacteriosis in humans. In contrast, piglets inoculated with the dps mutant were not colonized and remained normal throughout the study period. Mucosal lesion production was restored in piglets inoculated with the complemented Dps mutant strain. Based on these results, we conclude that the C. jejuni Dps homolog is a virulence factor in the production of campylobacteriosis, and warrants further investigation.