Background: Transthyretin Amyloidosis (ATTR) is a common cause of both cardiomyopathy and carpal tunnel syndrome, with many patients needing carpal tunnel release (CTR). Although tafamidis is now an approved treatment of ATTR cardiomyopathy, insurers in most provinces require biopsy confirmation of amyloidosis. Endomyocardial biopsy is often the chosen approach due to optimal sensitivity, albeit with risk of serious adverse events such as stroke, cardiac tamponade, and arrhythmias. CTR may present an ideal opportunity for obtaining amyloidosis biopsy confirmation. Methods: ATTR patients undergoing CTR had biopsy of their transverse carpal ligament (TCL) and/or flexor tenosynovium to assess the sensitivity of both sites for biopsy confirmation of amyloidosis. Results: Twelve patients consecutively underwent biopsies during CTR, with 4 (33%) having bilateral CTR and biopsy. Among 16 TCL biopsies and 14 tenosynovium biopsies, 100% demonstrated amyloid deposition. Another patient had isolated tenosynovium biopsy without CTR and also demonstrated amyloidosis. There were no serious adverse events, and 1/13 (8%) had wound dehiscence requiring repeat suturing. Conclusions: Biopsy of the TCL and/or tenosynovium during CTR is safe, cost-effective, and sensitive, and may represent an alternative to endomyocardial biopsy in patients requiring tissue confirmation for tafamidis approval. ATTR patients eligible for tafamidis may benefit from early neurology assessment.