BACKGROUND: Stress is a common feature of life and has routinely been linked with negative health outcomes. However, meaning has been identified as a possible buffer against stress. PURPOSE: The purpose of the current study was to examine whether the relationship between stress and health was mediated by meaning in life. METHODS: Drawing from Wave 1 of the Landmark Spirituality and Health Study, a nationally representative sample of adults, participants (N = 1871) reported their level of stress in the past 12 months, current meaning in life, health (measured as minor symptoms, major conditions, and overall health), and provided a blood sample for biomarker of immune system functioning (i.e., presence of Epstein-Barr virus antibodies). RESULTS: Results revealed an indirect effects model in which stress was inversely associated with meaning. Higher meaning was related to better self-reported health (across minor, major, and overall health measures), which, in turn, was associated with better immune system functioning. CONCLUSIONS: These findings suggest that part of the negative effect of stress on health is accounted for by reduced meaning.