This study aimed to investigate the effectiveness of a 3D-modeling-based customized off-loading cushion to prevent pressure ulcers in people with spinal cord injury (SCI) using wheelchairs. The study included five people with SCI who use the traditionally manufactured customized off-loading cushions. As part of the test, each subject sat on three types of pressure-relief cushions, and the pressure between the seating surface and cushion was measured for 60[Formula: see text]min. The average measured pressure values were compared, and the change in pressure with time was analyzed to verify the clinical effect. The results showed that the CAD/CAM-based customized off-loading cushion exhibited a better decrease in pressure and pressure distribution effect on the ischial tuberosity and coccyx than the adjustable air cushion but did not differ much from the traditionally manufactured customized off-loading cushion. The clinical and economic effectiveness of the customized off-loading cushion based on the computer-aided design and manufacturing (CAD/CAM) technology was analyzed and tested on people with SCI. An occupational therapist evaluating the client followed by designing the customized off-loading strategy has no difference in terms of clinical effect compared to the traditional manufacturing method. However, time, effort, and cost should be considered when choosing an intervention strategy.