Stress is unavoidable in aquaculture and hence strains of fish that are resilient and adaptable to stress need to be developed. In teleosts, cortisol is considered the primary stress hormone and often increases in cortisol concentration correspond to a stress response. The objective of this study was to assess if cortisol responsiveness to stress in channel catfish (Ictalurus punctatus) influences susceptibility to Enteric Septicemia of Catfish (ESC) caused by Edwardsiella ictaluri under controlled conditions. Juvenile channel catfish were subjected to standardized hypoxia stress (1.8 mg L-1 of dissolved oxygen) to classify them as either low responders (LR) or high responders (HR) based on their plasma cortisol concentration. Fish in both groups were held either in individual or co-cultured in 80-L aquaria and were challenged with virulent E. ictaluri by an in situ bath immersion to evaluate their susceptibility to the pathogen. At the end of the 21-day challenge, mean percent mortality of LR fish (38.1%) was significantly lower than that of HR fish (59.0%). Mean mortality of channel catfish was positively related to their mean plasma concentration of cortisol. An increase in susceptibility of HR fish to ESC may be the result of their higher responsiveness to standardized stress. Hence, the results of the present study suggest LR fish may be more resilient and adaptable to stressful conditions than HR fish.