It has been observed that patients with carpal tunnel syndrome (CTS) who also experience emotional distress, depression, or anxiety report more severe symptoms. As patients' own perspectives about their health increasingly are guiding treatment decisions, it seems important to study the simultaneous association of psychological distress and neuropathology with hand disability in patients who have CTS, as this may help prioritize and sequence management steps. What are the relationships among validated scores for (1) depression, (2) anxiety, (3) pain catastrophizing, and (4) nerve electrodiagnostic severity with measures of hand disability in patients with confirmed CTS? Between 2017 and 2019, we evaluated 116 patients for CTS in a referral urban hospital in Mashhad, Iran. Of those, we considered 85% (99) as potentially eligible by considering the following Electromyography-Nerve Conduction Study (EMG-NCS) diagnostic criteria: sensory latency ≥ 3.5 Ms, median-ulnar latency difference ≥ 0.5 Ms, motor latency ≥ 4.2 Ms, and abnormal EMG findings in the opponens pollicis muscle (neurogenic motor unit action potentials, positive sharp waves, or fibrillation). A further 13% (15 of 116) were excluded because of nonidiopathic CTS and prior surgery, and another 12% (14 of 116) were lost because of incomplete datasets, leaving 60% (70 of 116) for final inclusion in this cross-sectional study. In all, 89% of patients were women with total mean age of 47 years. We measured depression and anxiety using the Hospital Anxiety and Depression Scale (HADS) questionnaire (scored from 0 to 21, with a minimum clinically important difference [MCID] of 1.7 points), and we evaluated patients' state of mind regarding pain using the Pain Catastrophizing Scale (PCS) (scored from 0 to 52). Higher scores on these questionnaires represent more distress and pain catastrophizing. Hand disability was assessed with Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire outcomes (scored from 0 [no disability] to 100 [most severe disability]; MCID of 15 points), Likert pain score (from 0 to 10), and grip/pinch dynamometry results. Correlational analyses were conducted once among HADS and PCS scores and again among EMG-NCS indices with pain and disability variables to answer our first, third, and fourth questions, respectively. Regression analysis was performed to assess the percentage of variance in QuickDASH and pain severity, which could be explained by psychological and electrodiagnostic factors. We did not include grip and pinch in our multivariable model (regression analysis) as dependent variables because they did not correlate with any of psychological or EMG-NCS variables (all p values > 0.1). Significance was set at p < 0.05. Correlational analysis showed that the scores of all three psychological questionnaires correlated with the QuickDASH score (r = 0.50, 0.42, and 0.53 for HADS-A, HADS-D, and PCS, respectively; p < 0.001 for all three), while EMG-NCS parameters had no correlation with QuickDASH and pain scores. We also found that 37% of the variance in QuickDASH score can be explained by HADS and PCS scores (r2 = 0.37; p < 0.001). Evaluation and treatment of psychological distress before deciding on elective surgery for CTS is important because patient-reported disability-often used as a factor in surgical decision-making-is substantially correlated with emotional distress. Future prospective, controlled studies on this topic are recommended; ideally, these should evaluate psychological interventions specifically to ascertain whether they improve patients' ratings of hand disability. Level III, prognostic study.