Resilience may mitigate impact of secondary symptoms such as pain and fatigue on quality of life in persons aging with disability. This study examined resilience in a large sample of individuals with disabling medical conditions by validating the Connor–Davidson Resilience Scale, obtaining descriptive information about resilience and evaluating resilience as a mediator among key secondary symptoms and quality of life using structural equation modeling. Results indicated that the measure’s psychometric properties were adequate in this sample. Resilience was lowest among participants who were middle-aged or younger, and participants with depression. Resilience mediated associations between secondary symptoms and quality of life.