The detection of psychological variables with a positive impact on health during middle age is of great interest. The data of 393 middle-aged participants (aged 35–45 at T1 and 45–55 at T2) of the National Survey of Midlife Development in the United States (MIDUS) were analyzed to investigate the associations between health, optimism, positive affect, social support, and a cumulative burden score. Results show a positive association of the protective factors and a predictive value of positive emotions on health over time. The burden score showed no unique association with health. Overall, the predictors explained 17% of the variance of physical health and 33% of the variance of mental health. These findings emphasize the importance of investigating protective pathways.