Aims: Adaptive phenotypes of enteric bacterial pathogens in response to in vivo-mimicking stress conditions are important because of their potentiality to enhance stress resistance and ameliorate measures intended to control transmission and infectivity. Salmonella enterica serotype Enteritidis (S. Enteritidis) encounters a variety of such environments throughout its infection cycle, including high concentrations of the short-chain fatty acid, Propionate (PA), during food processing and within the gut of infected hosts. With this study, we aimed to elucidate the significance of PA adaptation on stress resistance in S. Enteritidis. Methods and Results: We have shown (utilizing in vitro stress assays) that S. Enteritidis grown to stationary phase in the presence of PA has a dramatically enhanced resistance to commonly encountered in vivo stressors, including extreme acidity and oxidative/nitrosative stresses when compared to unadapted salmonellae. However, competitive infection between PA adapted and unadapted cells within a murine model showed that adapted cells were at a distinct disadvantage in vivo, resulting in decreased caecal colonization in infected mice. Conclusions: Our results suggest that, while long-term PA adaptation induces strong resistance to specific stresses in vitro, it also reduces the overall infectivity of the adapted cells by inhibiting the organism's colonization ability. Significance and Impact of the Study: In S. Enteritidis, PA adaptation is strongly associated with the induction of stress-resistant phenotypes in vitro. Enhanced stress resistance ex vivo may increase environmental persistence and/or the overall transmissibility of this pathogen, while overall the virulence of the pathogen is likely to be hindered as a result of the decreased colonization ability of PA-adapted S. Enteritidis.