The purposes of this study were to examine the influence of personality on mental and physical health of spouse caregivers and to determine whether there were differences in such influences depending on disease context. The disease contexts compared were Alzheimer’s disease (AD) and Parkinson’s disease (PD; with no coexisting dementia)—both chronic, degenerative diseases of later life. It was predicted that personality would be related to mental and physical health, directly and indirectly, and that AD caregivers would have higher levels of perceived stress and worse mental and physical health outcomes. Participants in the study were 175 caregivers (88 AD; 87 PD) living at home with their ill spouses. The data provided an excellent fit to the hypothesized model of the relationships between personality, disease group, social support, perceived stress, and mental and physical health. Seventy-eight percent of the variance in mental health was accounted for and 35% of the variance in physical health was explained. Personality had significant direct and indirect effects on mental health and significant indirect effects on physical health. As predicted, AD caregivers had significantly worse mental health than PD caregivers; however, AD caregivers had better physical health than PD caregivers, controlling for other variables in the model. These results are discussed in relation to the existing caregiving and behavioral medicine literature. Future research should include different domains of personality—states and longer term self-regulatory processes in addition to traits—to advance models of caregiving processes further.