PURPOSE: Informal caregivers play a critical role in the care of individuals who are aging or have disabilities and are at increased risk for poor health outcomes. This study sought to determine whether and to what extent: (1) global stress and health-related quality of life (HRQoL) differed between caregivers and non-caregivers; (2) global stress mediated the relationship between caregiving status and HRQoL; and (3) caregiver strain (i.e., stress attributable to caregiving) was associated with worse HRQoL after accounting for global stress. METHODS: Cross-sectional data were from the 2008-2010 Survey of the Health of Wisconsin, a representative sample of adults aged 21-74 years. Participants (n = 1,364) completed questionnaires about caregiving status, sociodemographics, global stress, and HRQoL. Staged generalized additive models assessed the impact of caregiving on HRQoL and the role of caregiver strain and global stress in this relationship. RESULTS: In the last 12 months, 17.2% of the sample reported caregiving. Caregivers reported worse mental HRQoL than non-caregivers (β -1.88, p = 0.02); global stress mediated this relationship (p < 0.01). Caregivers with the highest levels of strain reported worse mental and physical HRQoL (β -7.12, p < 0.01), and caregivers with the lowest levels of strain reported better mental HRQoL (β 2.06, p = 0.01) than non-caregivers; these associations were attenuated by global stress (p < 0.01). CONCLUSION: Global stress, rather than caregiving per se, contributes to poor HRQoL among caregivers, above and beyond the effect of caregiving strain. Screening, monitoring, and reducing stress in multiple life domains presents an opportunity to improve HRQoL outcomes for caregivers.