Physical injuries are common occurrences that can have substantial implications for personal, emotional, and social functioning. A recent study reported higher prevalence of common illnesses and reduced health-related quality of life (HRQL) in injury victims. Based on these findings, the present study examined the role of the antibody immunoglobulin A (IgA) and the stress hormone cortisol in the association between injury and health. Additionally, the role of daily life stress and dispositional optimism in this association was examined. Thirty-seven victims of injury (e.g., fractures and burns) and 41 noninjured participants were assessed for cortisol and IgA levels and completed a battery of questionnaires assessing illness prevalence, HRQL, perceived stress, and optimism. Injured participants reported higher prevalence of illness and poorer HRQL compared with noninjured participants; however, changes in cortisol or IgA levels did not explain this increase in illness. Correlations between perceived stress and HRQL were stronger in injured participants compared with noninjured controls, indicating that injured individuals are more affected by stress. Dispositional optimism was lower in injured participants, and optimism buffered the negative effect of stress on HRQL. Accordingly, it is suggested that optimism played a protective role against the negative consequences of stress in injured individuals, thus improving HRQL.