Social relationships are postulated to benefit health through direct and stress-buffering effects. Positive dyadic coping, a spousal support process in which a couple works together to cope with the stressors that one or both partners are facing, is associated with reduced psychological distress. The goal of the present study was to evaluate the association between dyadic coping and inflammation, which is elevated under chronic stress and increases risk for health threats. It was hypothesized that positive dyadic coping would buffer the impact of chronic stress on perceived stress, and in turn reduce inflammation. Forty-four parents of children with an Autism Spectrum Disorder completed questionnaires that assessed relationship satisfaction, social support, and dyadic coping. Daily diaries assessed the occurrence of child behavior problems. Circulating C-reactive protein (CRP) was assessed using ELISA on dried blood spots. Hierarchical linear regression models evaluated the main and interactive effects of child behavior problems, and positive and negative dyadic on circulating CRP. Moderated mediation analyses evaluated the conditional indirect effect of dyadic coping on circulating CRP through perceived caregiving burden. Positive dyadic coping, but not negative dyadic coping, was uniquely associated with circulating CRP. Positive dyadic coping, but not negative dyadic coping buffered the impact of chronic stress on perceived caregiving burden. However, perceived stress did not explain the association between positive dyadic coping and inflammation. These data suggest that positive dyadic coping is a unique interpersonal process that reduces psychological distress and inflammation. Future research should evaluate interventions aimed at improving positive dyadic coping and inflammation among couples experiencing chronic stress.