Statement of the problem. Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. It affects over 2.5 million people worldwide and approximately 350,000 Americans with new cases diagnosed weekly. MS significantly impacts activity participation, general health status, and quality of life. An extensive literature review reveals a gap in the rehabilitation and MS literature regarding evidence of the effectiveness of occupational therapy rehabilitation programs or occupational therapy wellness programs to improve the activity participation, general health and well-being, and quality of life for people living with MS. Methods. This randomized controlled trial (RCT) compared the long-term impact of an occupational therapy rehabilitation program, an occupational therapy wellness program, and a social activity program (control), on the occupational performance, general health and well-being, and quality of life of people living with MS, through repeated measures. Assessment tools used to measure occupational performance, general health and well-being and quality of life were the Occupational Self-Assessment, the Short Form-36 version 2 and the Quality of Life Inventory. Quality of life is a primary outcome in the provision of healthcare services for the chronically ill, and is the predominant measure in this clinical research, hence the choice of these assessment tools. Results. The effect of each of the group programs, rehabilitation, wellness and a social activity group was compared. Data were analyzed with MANOVA. The results yielded that the occupational therapy wellness group demonstrated a statistically significantly positive difference in the mental component summary measure of the SF-36v2 over the occupational therapy rehabilitation group (p = .093), two months post intervention. The results further revealed that the occupational therapy wellness group demonstrated a statistically significantly positive difference in the environmental impact scale of the OSA over the occupational therapy rehabilitation group (p = .115) and the social activity group (p = .065), over a period of three months. Conclusions. In this study an occupational therapy wellness approach showed statistically significantly positive effects on the environmental impact and mental health of people with MS over the long-term. This study also demonstrated the clinical significance associated with an occupational therapy rehabilitation and an occupational therapy wellness approach. These findings therefore contribute to evidence-based practice for the most effective occupational therapy interventions for persons with MS. This study was supported by grant #NSU012001 from the National Multiple Sclerosis Foundation and the Nova Southeastern University President's Scholarship Award 2001.

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