Regular exercise reduces functional loss associated with multiple sclerosis (MS). However, the impact of exercise on inflammatory mediators associated with disease activity remains relatively unexplored. The purpose of this study was to determine whether ambulatory MS subjects would respond similarly to aerobic cycle training compared to matched controls on circulating immune variables, interleukin (IL)-6, tumor necrosis factor (TNF)- and interferon (IFN)- . Eleven MS and eleven non-MS control subjects (8 women and 3 men in both groups) matched in age, height, body mass, body fat and VO_2peak completed the study. Subjects completed 30 minutes of cycle ergometry at 60% of VO_2peak, 3 day/week for 8 weeks. Plasma cytokine concentrations were determined before and after exercise at weeks 0, 4 and 8. IL-6 at rest tended to decrease (p=0.08) with training in both groups. Resting plasma TNF- tended to be higher in MS compared to controls throughout the study (p=0.08). MS subjects showed elevated resting TNF- in MS at the end of the 8 week program (p=0.04), while resting TNF- remained unchanged in controls (p>0.05). Resting plasma IFN- at rest was elevated in MS subjects (p=0.008) and unchanged in controls at the end of the intervention (p>0.05). The response of plasma IL-6, TNF- and IFN- after a single bout of exercise was similar between MS and control subjects (p>0.05). Additional research to understand the impact of exercise on immune variables in MS is warranted.