Objective: This study was conducted to determine which factors (clinical and demographic) are associated with mental and physical health-related quality of life (HRQOL) for caregivers of older persons with multiple sclerosis (MS). The Andersen’s Healthcare Utilization Model guided this study. Knowledge of identified predictors of HRQOL may prompt nurses who care for persons with MS to address these issues and provide supportive care. Methods: A cross-sectional descriptive design was used to examine the relationship between patient with MS and caregiver clinical and demographic factors with caregiver physical and mental HRQOL. Patients with MS aged 60 years or older and their caregivers from four MS centers on Long Island, New York, self-selected into this study (n = 102). A caregiver survey was administered that collected demographic information and included validated questionnaires measuring HRQOL, caregiver burden, and caregiver perception of risk for neuropsychological impairment of patients with MS. Patient surveys collected demographic information and validated questionnaires measuring cognition, depression, and disability. Multivariate linear regression was used to examine patient and caregiver variables to explain caregiver physical and mental HRQOL. Results: The caregivers in this study were older (mean age = 61 years) with existing comorbidities. We found that caregiver mental HRQOL was negatively associated with patient depression and, surprisingly, positively associated with caregiver burden and caregiver comorbidity of heart disease. Caregiver physical HRQOL was negatively associated with caregiver comorbidities of arthritis and diabetes and lower household income. Conclusion: The challenges older caregivers face when caring for older persons with MS have been shown to affect their mental and physical QOL. Nurses who care for older patients with MS will increasingly rely on older caregivers to provide patient-centered interventions. This descriptive study, based on the Anderson theoretical model, provides insight on factors impacting older caregivers’ HRQOL. Further research is necessary to elucidate the types of interventions that support them as they care for older patients with MS.