Wheelchair users with spinal cord injury (SCI) have a high risk of developing shoulder pain, caused by rotator cuff disease. Platelet-rich plasma (PRP) is a potential treatment after conservative treatments fail and prior to surgical intervention; however, it has not been tested in wheelchair users who have recalcitrant shoulder pain associated with rotator cuff disease. The objective of this pilot project was to test the safety and potential treatment effect of an ultrasound-guided PRP injection for shoulder pain in the aforementioned population. Prospective, quasi-experimental. Clinical research center. Six wheelchair users with SCI (3 paraplegia, 3 tetraplegia) who had chronic shoulder pain due to rotator cuff disease (presence of anterior shoulder pain, positive physical examination tests for rotator cuff disease, and tendinopathy demonstrated by ultrasound) and failed at least six months of conservative treatment. Ultrasound-guided PRP injection into pathological shoulder tendons, targeting the supraspinatus. Subjects were provided a standardized stretching and strengthening program and were followed for 4, 8, 12, and 24 weeks post-intervention with outcomes collected at each time-point. Wheelchair User's Shoulder Pain Index (WUSPI); pain Numerical Rating Scale (NRS); physical and ultrasound examinations for supraspinatus tendinopathy; 5-point patient global impression of change (PGIC). WUSPI (69.9%, P < 0.001), NRS (49.6%, P < 0.01), and physical exam scores (35.7%, P < 0.01) decreased 24 weeks after treatment. Participants reported overall improvement in their status as a result of the treatment. No adverse events were noted, and no changes in ultrasound markers for tendinopathy were observed. A single, ultrasound-guided PRP injection into the supraspinatus tendon, followed by a stretching and strengthening exercise program, was safe and provided improvements in shoulder pain outcome measures in this sample for 24 weeks. Lack of blinding, short-term follow-up, and a suitable control group warrant a larger randomized controlled trial. NCT01355549.