Objective: Personality influences many aspects of the health process, including associations with possible mechanisms such as inflammation and health behaviors. It is currently unclear to what extent, if any, the Big Five personality traits uniquely impact later health through independent pathways of inflammatory biomarkers and health behaviors. Furthermore, it is unknown if this relationship varies for self- and informant-reports of personality. Methods: Using data from older adults (N = 1,630) enrolled in the St. Louis Personality and Aging Network study, we test whether self- and informant-reported personality (Big Five personality traits) show consistent associations with inflammation (i.e., IL-6, CRP, and TNF-α). Further, we tested whether inflammation and health behavior indirectly link personality to health outcomes through independent or shared pathways using longitudinal mediation in a structural equation modeling framework.Results: Self- and informant-reports of personality uniquely predicted future levels of inflammatory biomarkers (self bs range from -0.11 to 0.07; informant bs range from -0.15 to 0.11). Additionally, both reports of personality impacted health through biomarker and health behavior pathways. Effects were primarily found for conscientiousness (indirect effect bs range from 0.01 to 0.04) and neuroticism (indirect effect bs range from -0.01 to -0.02) and IL-6 and CRP were the biomarkers most repeatedly linked with the Big Five personality traits and health. Conclusions: Findings highlight the potential benefits of using of multiple assessments of personality and the importance of examining multiple, distinct pathways by which personality might influence later health in order to more fully understand the mechanisms underlying this relationship.