Objective: The goal of this study was to examine the role of stress and four different types of social support in satisfaction with life (SWL) among adults with rare diseases (RDs). We examined whether support is directly related to SWL (main effects model) or related through moderating the inverse relationship between stress and SWL (stress-buffering hypothesis). Method: Data came from a cross-sectional survey of adults living in the United States diagnosed with any RD. Participants (n = 1,203) filled out measures of stress, four short-form scales of social support (emotional, informational, tangible, companionship), and SWL. Hierarchical multiple regression was used to test both the main effects model and stress-buffering hypothesis. Results: Controlling for age, gender, years since diagnosis, and symptom severity, emotional support, but not informational or tangible support, positively predicted SWL. Companionship support was related to SWL over and above other factors. Stress negatively predicted SWL, but none of the types of support moderated this relationship. Conclusion: Results suggest companionship and emotional support are beneficial to individuals with RDs regardless of their stress levels. Intervention research should focus on ways to foster more companionship and emotional support to improve SWL in this underserved population.