Multiple sclerosis (MS) is a chronic, unpredictable, progressive, and disabling autoimmune disease with significant neurodegenerative and inflammatory components. To effectively treat and care for older persons with MS, it is essential to examine the factors associated with a decrease in their quality of life. Typically, MS is diagnosed between 20 and 50 years old. Although not a fatal disease, the natural history data of persons with MS reveal survival approximately 38 years after diagnosis. With the advent of disease-modifying therapies, life-span has increased substantially over the past 2 decades among people with MS. Approximately 90% of people with MS now in their 20s may live into their 70s. Their quality of life as an older adult will be impacted by what we learn today. Currently, approximately a quarter of people with MS are mature adults over 65 years old. Older adults with MS are more likely to have a decreased health-related quality of life (HRQOL). HRQOL is a multidimensional construct that refers to an individual’s physical functioning, ability to perform activities of daily living, sense of well-being, satisfaction with life, perception of psychological status, and social functioning. This article focuses on the current literature in HRQOL in older persons with MS. A specific aim is to examine the factors associated with a decreased QOL in older persons with MS. Nursing screening and implementation of interventions that may reduce these factors and improve function of patients will be discussed. Although measures to improve HRQOL do not substitute for treatment of the disease, knowledge of factors that reduce HRQOL is essential to understand patient perceptions of their health and disease.