Purpose: To measure the impact of stroke on quality of life (QOL), and analyze whether race, gender, age, income, or living alone moderated those changes, using prospective longitudinal methods. Methods: Participants in the REasons for Geographic and Racial Differences in Stroke study without history of stroke completed baseline SF-12 Mental (MCS) and Physical Component Summary (PCS) measures and a depression scale. Measures were repeated (M = 1231 days later) by 136 participants after an incident medically documented stroke and by 136 demographically matched stroke-free controls. Results: Stroke participants showed significant worsening than controls in all three QOL measures. Controls also declined significantly in PCS. Standardized effect sizes for stroke versus control participants after adjusting for covariates were similar across the three measures and ranged from .366 to .465 standard deviation units. Stroke survivors who lived alone were at greater risk for increases in depressive symptoms. Conclusions: Multiple declines in QOL occur after stroke, and social isolation heightens risk for increasing depression after stroke. Our prospective design and use of a population-based sample with matched controls suggests similar effects in both physical health and mental health QOL domains and offers unique strengths in understanding the impact of stroke on QOL. © 2010 Springer Science+Business Media B.V.