Purpose: To investigate effects and working mechanisms of low-intensity aerobic wheelchair exercise on fitness, (upper-body) health and active lifestyle in inactive persons with chronic spinal cord injury (SCI). Methods: A multicenter randomized-controlled trial (RCT) in 40 inactive manual wheelchair users (aged 28-65y) with chronic paraplegia or tetraplegia (time since injury >10y). Subjects will be randomly assigned to an intervention or a control group. The intervention will consist of 16 weeks (2 times per week, 30 min per session) of low-intensity aerobic handrim wheelchair exercise (30-40% HRR) on a treadmill. Repeated measurements will be performed before starting the intervention or entrance of the control group, and after week 8, 16 and 42 following the start. The primary outcome will be wheelchair-specific physical fitness. Secondary outcomes will be upper-body pain and discomfort, shoulder load, propulsion technique, wheelchair skill performance and physical activity levels. Conclusions: Results of this first RCT on low-intensity aerobic wheelchair exercise for inactive persons with chronic SCI can improve SCI-specific exercise guidelines and provide an evidence-base for an aftercare program aimed at preserving fitness, health and active lifestyle of persons aging with SCI.