Background The Patient-reported Outcome Measurement Information System (PROMIS) continues to be an important universal patient-reported outcomes measure (PROM) in orthopaedic surgery. However, there is concern about the performance of the PROMIS as a general health questionnaire in hand surgery compared with the performance of region-and condition-specific PROMs such as the Michigan Hand Questionnaire (MHQ) and the Boston Carpal Tunnel Questionnaire (BCTQ), respectively. To ensure that PROMIS domains capture patient-reported outcomes to the same degree as region-and condition-specific PROMs do, comparing PROM performance is necessary. Questions/purposes (1) Which PROMs demonstrate high responsiveness among patients undergoing carpal tunnel release (CTR)? (2) Which of the PROMIS domains (Physical Function [PF], Upper Extremity [UE], and Pain Interference [PI]) demonstrate concurrent validity with the HHQ and BCTQ domains? Methods In this prospective study, between November 2014 and October 2016, patients with carpal tunnel syndrome visiting a single surgeon who elected to undergo CTR completed the BCTQ, MHQ, and PROMIS UE, PF, and PI domains at each visit. A total of 101 patients agreed to participate. Of these, 31 patients (31%) did not return for a followup visit at least 6 weeks after CTR and were excluded, leaving a final sample of 70 patients (69%). We compared the PROMIS against region-and condition-specific PROMs in terms of responsiveness and concurrent validity. Responsiveness was determined using Cohen's d or the effect-size index (ESI). The larger the absolute value of the ESI, the greater the effect size. Using the ESI allows surgeons to better quantify the impact of CTR, with a medium ESI (that is, 0.5) representing a visible clinical change to a careful observer. Concurrent validity was determined using Spearman's correlation coefficient with correlation strengths categorized as excellent (> 0.7), excellent-good (0.61-0.70), good (0.4-0.6), and poor (< 0.4). Significance was set a priori at p < 0.05. One of the authors (DNB) reports receiving grants from Alpha Omega Alpha (less than USD 10,000), outside the submitted work. One of the authors (WCH) reports being the ASSH Hand-e, Editor, outside of the submitted work (10,000 to USD 100,000, USD). Two authors (JRH and BM) certify that they have no commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. Each author certifies that his institution approved the human protocol for this investigation and that all investigations were conducted in conformity with ethical principles of research.