Religiousness and spirituality (R/S) are associated with lower morbidity and mortality, yet the physiological mechanisms underlying these associations are under-studied. Chronic inflammation is a plausible biological mechanism linking R/S to downstream health given the sensitivity of the immune system to the social environment and the role of inflammation in many chronic diseases. The purpose of the present study was to examine associations between multiple R/S dimensions and two markers of chronic inflammation, interleukin-6 (IL-6) and C-reactive protein (CRP). In this cross-sectional study, data came from biological subsamples of two cohorts from the Midlife in the United States (MIDUS) Study (combined N = 2,118). Predictors include six R/S measures (service attendance, spirituality, private religious practices, daily spiritual experiences, religious coping, and R/S-based mindfulness). Outcomes include log-transformed IL-6 and CRP. Covariates include age, gender, cohort, race, educational attainment, body mass index (BMI), smoking status, and physical activity. Older adults, women (vs. men), non-White (vs. White) adults, those with higher BMIs, current smokers, and those not meeting physical activity guidelines had significantly higher IL-6 and CRP. In fully adjusted models, greater spirituality, daily spiritual experiences, religious coping, and R/S-based mindfulness were associated with lower IL-6. Higher spirituality was also associated with lower CRP. Many dimensions of R/S may be health protective for adults given their associations with lower levels of chronic inflammation. Findings underscore the importance of examining multiple dimensions of R/S to understand mechanistic pathways.