The purpose of this study was to determine whether muscle balance is influenced by fatigue in a recordable way, toward creating novel defensive activity strategies for manual wheelchair users (MWUs). Wheelchair propulsion to a point of mild fatigue, level 15 on the Rating of Perceived Exertion scale, was investigated at two different speeds. Surface electromyographic (EMG) activity of 7 muscles was recorded on 14 nondisabled participants. Kinetic variables were measured using a SmartWheel. No significant effect was found of percentage endurance time on kinetic variables for the two propulsion speeds. Fatigue-related changes in the EMG spectra were identified as an increase of EMG intensity and a decrease of mean power frequency as a function of percent endurance time for the tested muscles under both fast and slow speed conditions. The greater increases in activity for propulsive muscles compared with recovery muscles during fast speed wheelchair propulsion indicated muscle imbalance associated with fatiguing wheelchair propulsion. This study shows how kinetic and EMG information might be used as feedback to MWUs to ensure that they conduct activity in ways that do not precipitate injury.