The purpose of this study was to determine the safety and effectiveness of office-based carpal tunnel release with ultrasound guidance (CTR-US). In this prospective multicenter observational study, patients were treated with CTR-US in an office setting. Outcomes were time to resume normal daily activities, time to return to work, Boston Carpal Tunnel Questionnaire Symptom Severity Scale and Functional Status Scale scores, Michigan Hand Questionnaire, Numeric Pain Scale, EuroQoL-5 Dimension 5-Level score, procedure satisfaction, and adverse events over 6 months. A total of 149 participants (226 hands) from seven centers underwent office-based CTR-US. The mean age was 58 years, 52% were women, and 68% were employed. The mean incision length was 5 mm, 52% had simultaneous bilateral procedures, and wide-awake local anesthesia no tourniquet was used in all cases. All procedures were completed as planned, with no conversions to open repair and mean intraoperative pain severity of 1.6 ± 1.5. The median time to resume normal activities was 2 days (interquartile range: 1-4 days) and return to work was 4 days (interquartile range: 1-5 days). Over 6 months, Boston Carpal Tunnel Questionnaire Symptom Severity Scale decreased by a mean of 1.7 points, Boston Carpal Tunnel Questionnaire Functional Status Scale decreased by 1.1 points, Michigan Hand Questionnaire Global score increased by 35 points, Numeric Pain Scale decreased by 3.7 points, and EuroQoL-5 Dimension 5-Level score increased by 0.11 points. At 6 months, 94% reported procedure satisfaction. Unilateral and simultaneous bilateral procedures were similarly effective. There was one (0.4%) adverse event, a nerve contusion treated with neurolysis and nerve wrap where the patient fully regained normal function within 7 weeks. There were no revisions for persistent or recurrent carpal tunnel syndrome symptoms. Office-based CTR-US, performed either unilaterally or as simultaneous bilateral procedures, is well tolerated with a low complication rate and associated with rapid recovery, sustained improvement in symptoms and function, and high procedure satisfaction. Therapeutic III.