Fatigue is a prevalent and debilitating symptom that affects up to 97% of individuals with multiple sclerosis (MS). It can negatively influence the socioeconomic status, activities of daily living and quality of life for the affected individuals. Fatigue is multidimensional and abstract, thereby making it complex to understand, target and treat. Over the past 20 years, physical activity has become more recognized as a management method that could help with the alleviation of fatigue. One of the reasons could be due to the anti-inflammatory effects of exercise. However, due to the multi-factorial nature of fatigue and the heterogeneity of the training intervention protocols, the potential mechanisms that underlie the relationship between fatigue and exercise are still not fully understood. In 2013, Latimer-Cheung and colleagues developed an evidence based physical activity guideline (PAGs) for people with MS. Since then, studies have shown consistent beneficial effects of exercise on reducing fatigue in people with MS by adhering to the PAGs. To date, however, there are no published studies that examined the potential mechanism that underlie the beneficial effect of the PAGs on reducing fatigue. The primary purpose of this thesis was to evaluate the effects of adhering to the PAGs on fatigue in people with MS and to assess whether any exercise-induced changes in fatigue were associated with changes in inflammatory cytokines. The secondary purpose of this thesis was to evaluate the effects of exercise on depression, strength, aerobic fitness, muscular endurance and quality of life. This study had a wait-list control design. Participants with relapse remitting multiple sclerosis (RRMS) were recruited and randomized to begin with either a 12-week supervised exercise training program (G1) or a wait-list control period (G2). The training program involved at least 30 minutes aerobic training and resistance training for major muscle groups twice per week. The G2 group maintained their regular lifestyle. After 12 weeks, G1 reverted back to their usual lifestyle and G2 began their 12-week supervised exercise training. Following training, we found a reduction in fatigue and depression with increased strength and quality of life. No changes were observed in pro-inflammatory cytokines, aerobic fitness or muscular endurance. This is the first study that examined the underlying potential mechanism for the beneficial effects of exercise by adhering to the PAGs. Following the PAGs for 12 weeks results in significant improvements in fatigue, depression, strength and quality of life. However, our results do not support the role of inflammatory cytokines in mediating these improvements. / Thesis / Master of Science in Kinesiology