PURPOSE: To prospectively report the outcomes of open carpal tunnel release with respect to patient age and medical comorbidities. METHODS: Nine hundred fifty open carpal tunnel procedures in 826 patients (age range, 21-100 y) at a high-volume orthopedic surgery center were evaluated. Self-reported symptom severity and functional scores were collected using the validated Boston Carpal Tunnel Outcomes questionnaire preoperatively, and at 2 weeks, 6 weeks, and 12 weeks postoperatively. RESULTS: Patients demonstrated a significant improvement in symptom severity scores at 2 weeks and functional severity scores at 6 weeks. Documented patient medical comorbidities did not affect improvement after surgery. Patients with diabetes improved more slowly but were not significantly different at 6 weeks. Patients with workers' compensation insurance were significantly worse at baseline, 2 weeks, and 6 weeks but were not significantly different at 3 months. The risk of negative postoperative endpoints was slightly higher in patients with a medical comorbidity, though not statistically different. CONCLUSIONS: Significant improvements in symptom severity and hand function may be expected after open carpal tunnel release in the general population regardless of age, medical comorbidities, or workers' compensation status. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III.