The purpose of this study was to compare the objective, subjective, and radiographic responses of patients with carpometacarpal joint osteoarthritis (CMCJ-OA) wearing a prefabricated neoprene splint (PFN), which crosses the CMCJ and metacarpophalangeal joint, with those of patients wearing a custom-made thermoplastic short opponens splint (CMT), which crosses only the CMCJ. Patients ( N = 25) with first CMCJ stage I and II osteoarthritis were assigned randomly to wear either the PFN splint or the CMT splint for one week. After one week, the subjects rated their function in the splint and their satisfaction and pain levels on visual analogue scales. Pinch measurements were performed and x-rays were taken to assess carpometacarpal subluxation. The second splint was then applied for one week and all measures were repeated. The subjects rated the PFN splint significantly higher, and most reported that they would choose the PFN splint over the CMT splint for daily and long-term use. Both pain and function were improved with splinting, but the effect was amplified with the PFN splint compared with the CMT splint. Both splints reduced subluxation at the first carpometacarpal joint, but the CMT effect was greater. This study further supports current evidence that subjects with stage I and II first CMCJ-OA will have pain relief with thumb splinting. In addition, the PFN splint will provide greater relief when compared with the CMT splint. Furthermore, this study reveals that patients prefer the PFN splint to the CMT splint.