This study investigated the relationship between cognitive, psychological and physical symptoms of multiple sclerosis (MS) and independent living optimism among a sample of 5,082 adults with MS (females = 77.8%; Whites = 96.1%, age range 20 to 91 years). Data on physical, cognitive and psychological function were collected utilising standardised clinical measures including the Multiple Sclerosis Impact Scale-29, Perceived Deficits Questionnaire-5-Item version, and the Independent Living Optimism scale. Multiple regression analysis indicated that specific physical, psychological and cognitive factors contributed to the overall prediction model. The combined variables explained approximately 33% of the variance in independent living optimism. This study enables a specific, item-level understanding of the relationship between MS-related symptoms and independent living optimism, and provides important information for the development of targeted rehabilitation interventions.