Objective: The aims of the study were to examine whether fatigue-inducing wheelchair propulsion changes neuromuscular activation and propulsion biomechanics and to determine predictor variables for susceptibility to fatigue. Design: This study with a quasi-experimental, one-group, pretest-posttest design investigates a population-based sample of wheelchair users with a spinal cord injury (n = 34, age: 50.8 +/- 9.7 yrs, 82% males). Neuromuscular activation and propulsion biomechanics during treadmill propulsion at 25 W and 45 W were assessed before and after a protocol designed to cause fatigue. Results: With the induced fatigue, wheelchair users propelled with increased neuromuscular activation in the pectoralis major pars sternalis, deltoideus pars acromialis and upper trapezius (45 W, P < 0.05), and a slightly reduced push angle (25 W: 75-74 degrees, P < 0.05, 45 W: 78-76 degrees, P < 0.05). Wheelchair users susceptible to fatigue (47%) were more likely to have a complete lesion, to be injured at an older age, and had less years since injury. This group propelled in general with shorter push angle and greater maximum resultant force, had a greater anaerobic capacity, and had less neuromuscular activation. Conclusions: Compensation strategies in response to fatiguing propulsion could increase the risk for shoulder injury. Predictor variables for susceptibility to fatigue inform interventions preserving shoulder health and include lesion characteristics, propulsion technique, anaerobic capacity, and neuromuscular activation.