Background: Stroke is a major cause of long-term disability. Most stroke survivors return to their own home and need to be cared for by family members, most of whom are informal caregivers. Objectives: The aim of this study was to identify whether cognitive appraisal influences health-related quality of life. Methodology: A cross-sectional, descriptive, correlational design was used. Participants included 77 primary support persons, mean age = 59.47 years, who were younger than stroke survivors (mean age = 78.13 years). Data were collected between March–November 2012 and obtained through face-to-face interviews, using the Short-Form-36 Health Survey, Caregiver Burden Inventory, and five cognitive appraisal questions. In addition, the Barthel Index, Modified Rankin Scale, and Glasgow Coma Scale were used to assess patient disease severity. Hierarchical multiple regression analysis was used to identify predictors of health-related quality of life. Results: The results indicated that 61% of participants rated their health as poor or fair. Patient severity, gender of primary support person, age, employment, burden, and cognitive appraisal impact accounted for 45.8% of the variance in primary support persons’ physical component summary of health-related quality of life, with age, burden, and appraisal impact being the strongest of six predictors. In addition, burden and appraisal impact were the strongest of six predictors, explaining 18.1% of the variance in primary support persons’ mental component summary of health-related quality of life. Conclusions: The results of the current study further highlight the importance of cognitive appraisal on the stroke survivor’s primary support person’s health-related quality of life.