Objective: To evaluate muscle activation patterns and co-contraction around the knee in response to walking with modified gait patterns in patients with medial compartment knee-osteoarthritis (KOA). Design: 40 medial KOA patients walked on an instrumented treadmill. Surface EMG activity from seven knee-spanning muscles (gastrocnemius, hamstrings, quadriceps), kinematics, and ground reaction forces were recorded. Patients received real-time visual feedback on target kinematics to modify their gait pattern towards three different gait modifications: Toe-in, Wider steps, Medial Thrust. The individualized feedback aimed to reduce their first peak knee adduction moment (KAM) by ≥ 10%. Changes in muscle activations and medial/lateral co-contraction index during the loading response phase (10–35% of the gait cycle) were evaluated, for the steps in which ≥ 10% KAM reduction was achieved. Results: Data from 30 patients were included in the analyses; i.e. all who could successfully reduce their KAM in a sufficient number of steps by ≥ 10%. When walking with ≥ 10% KAM reduction, Medial Thrust gait (KAM − 31%) showed increased flexor activation (24%), co-contraction (17%) and knee flexion moment (35%). Isolated wider-step gait also reduced the KAM (− 26%), but to a smaller extent, but without increasing muscle activation amplitudes and co-contraction. Toe-in gait showed the greatest reduction in the KAM (− 35%), but was accompanied by an increased flexor activation of 42% and hence an increased co-contraction index. Conclusion: Gait modifications that are most effective in reducing the KAM also yield an increase in co-contraction, thereby compromising at least part of the effects on net knee load.