Seventy-three postmenopausal women with mild knee osteoarthritis were randomized to receive either a high-impact aerobic/step aerobics training program (n=35) or continue their usual activities as a non-training reference group (n=38). The primary outcome of interest was the change in systemic cytokine levels. Secondary outcomes included associations between cytokines and cartilage quality (MRI T2 mapping) and weekly leisure-time physical activity (LTPA) measured in MET-hours. Outcomes were assessed at baseline and after 12 months. Overall, the results of the study revealed no significant between-group differences in cytokine level changes. However, TNF-α changes correlated with cartilage T2 in the intervention group, and IL-10 changes were associated with cartilage T2 and LTPA in the reference group. A high-impact exercise regimen did not adversely affect systemic inflammation and may be a viable option for postmenopausal women with mild knee OA.