This study compared cardio-respiratory responses during running wearing a motion control shoe (MC) or a cushioning shoe (CU) in a cross-over single blinded design. Fourteen runners (10F/4M, age=27.3+/-5.1 years, body mass=64.1+/-12.2 kg, height=167.8+/-7.5 cm, VO (2)max=52.3+/-8.8 ml/kg/min) completed a 40-min run at approximately 65% VO (2) max under both shoe conditions. Oxygen uptake (mL/kg/min; L/min), minute ventilation (L/min), respiratory exchange ratio, and heart rate were measured at minutes 8-10, 18-20, 28-30 and 38-40 of exercise. Rating of perceived exertion was obtained at minutes 10, 20, 30 and 40. Two (footwear) by four (time) repeated measures ANOVAs showed no differences between footwear conditions in overall oxygen consumption (MC=36.8+/-1.5 vs. CU=35.3+/-1.4 mL/kg/min, p=0.143), minute ventilation (MC=50.4+/-4 vs. CU=48.5+/-3.8, p=0.147), respiratory exchange ratio (MC=0.90+/-0.01 vs. CU=0.89+/-0.01, p=0.331), heart rate (MC=159+/-3 vs. CU=160+/-3, p=0.926), or rate of perceived exertion. The design of motion control footwear does not appear to affect cardio-respiratory or perceived exertion responses during submaximal running. The findings are specific to the shoes tested. Nonetheless, the outcomes suggest that footwear selection to reduce certain overuse injuries does not increase the work of running.