Purpose: The study's purpose was to determine the effect of foot orthoses on neuromuscular control and the aerobic cost of running. Methods: Twelve recreational athletes ran for 1 h on a treadmill at a constant velocity (i.e., 10% higher than their first ventilatory threshold) with and without custom-molded foot orthoses, in a counterbalanced order. Surface EMG activity of five lower limb muscles, together with oxygen consumption and HR, was recorded at 8-min intervals, starting after 2 min, during the run. A series of neuromuscular tests including voluntary and electrically evoked contractions of the ankle plantar flexors was performed before and after running. Results: Peroneus longus root mean square amplitude decreased with time, independently of the condition (-18.9%, P < 0.01). Lower root mean square signal amplitude for vastus medialis (-13.3%, P < 0.02) and gastrocnemius medialis (-10.7%, P < 0.05), combined with increased peroneus longus burst duration (+14.7%, P < 0.05), occurred when running with orthoses. There was no main effect of the condition for oxygen consumption (P > 0.05), whereas HR was significantly lowered while wearing foot orthoses (-3%, P < 0.02). Maximal strength capacity (-9%, P < 0.01), normalized EMG activity (-17%, P < 0.001), and peak twitch torque (-14%, P < 0.01) declined from before to after exercise, independently of the condition. Smaller fatigue-induced decrements in the rate of torque development within the first 200 ms (-6% vs-33%, P < 0.01) were reported after running with foot orthoses. Conclusions: Wearing foot orthoses alters neuromuscular control during a submaximal 1-h treadmill run and partly protects from the resulting fatigue-induced reductions in rapid force development characteristics of the plantar flexors. However, these changes may be too small to alter the aerobic cost of running.