CONTEXT: Osteopathic manipulative treatment (OMT) has been recognized as a management option for carpal tunnel syndrome (CTS), although limited research exists to substantiate its effectiveness. OBJECTIVE: To evaluate the effectiveness of OMT in the management of CTS. METHODS: This single-blinded quasi-controlled trial was conducted at an academic institution. Participants with CTS underwent weekly OMT sessions for 6 consecutive weeks. The main outcome measures were the Boston Carpal Tunnel Syndrome Questionnaire (BCTQ), a sensory symptom diagram (SSD), patient estimate of overall change, electrophysiologic testing of the median nerve (trans-carpal tunnel motor and sensory nerve conduction velocity and amplitude ratio), and carpal tunnel ultrasound imaging of the cross-sectional area of the median nerve and transverse carpal ligament length and bowing. All outcome measures were administered to participants before the first OMT session. Immediately after the first session, electrophysiologic testing of the median nerve and ultrasound imaging of the carpal tunnel were repeated. After 6 weeks of OMT, all outcome measures were readministered. RESULTS: Results of the BCTQ revealed statistically significant improvements in symptoms and function after 6 weeks of OMT (F=11.0; P=.004), and the improvements tended to be more pronounced on the treated side. The drop in SSD scores after 6 weeks of treatment was statistically significant (F=4.19; P=.0002). Patient estimate of overall improvement of symptoms was statistically significant for the treated side. No statistically significant changes in electrophysiologic function of the median nerve, cross-sectional area of the median nerve, or transverse carpal ligament bowing were observed. After treatment, the increase in transverse carpal ligament length was statistically significant, but no side-to-side difference was detected. CONCLUSION: Osteopathic manipulative treatment resulted in patient-perceived improvement in symptoms and function associated with CTS. However, median nerve function and morphology at the carpal tunnel did not change, possibly indicating a different mechanism by which OMT acted, such as central nervous system processes.