The purpose of this study was to relate mechanical parameters, muscular activity and measured running economy (RE) during treadmill running to muscular work derived from a musculoskeletal model. Participants were tested in three systematically modulated shoes. Methods: Subjects performed three trials in one testing session. Each session consisted of 16 min running on a treadmill, in each of the three modified shoes at a constant running speed (lateral wedge, neutral and medial wedge under the heel of running shoe). A VO2 analyser system was used to monitor oxygen consumption. Sagittal plane and rearfoot kinematics were assessed using 3D high-speed video system and a rearfoot goniometer. Muscle activations were recorded using bipolar surface EMG on eight muscles of the right leg. Results: Oxygen consumption was not significantly changed by inserts. However, muscle activity of soleus, tibialis anterior and biceps femoris were increased for the lateral insert. While model calculations reflected the measured changes in individual muscles the overall work did only partly reflect the measured metabolic energy