Purpose: This study aimed to determine whether Patient-Reported Outcome Measurement Information System (PROMIS) Physical Function and Pain Interference scores varied at presentation for specialty care by nontrauma hand condition. The secondary aim was to compare PROMIS scores with a reference standard, the Quick–Disabilities of the Arm, Shoulder, and Hand (QuickDASH), regarding the magnitude and direction of score differentials among diagnoses. Methods: PROMIS Physical Function and Pain Interference scores were analyzed from 1,471 consecutive new adult patient clinic visits at a tertiary orthopedic hand clinic presenting with 1 of 5 nontrauma hand conditions. A 5-point difference on PROMIS assessments was presumed to be clinically relevant. A random sample of 30 QuickDASH scores from each diagnostic group was evaluated for score differentials among groups. We also measured the correlation between PROMIS and QuickDASH scores. Results: Patients with carpal tunnel syndrome and thumb basal joint arthritis reported worse physical function and more pain interference, whereas those with Dupuytren contractures and ganglion cysts reported less pain and better function. For both domains, patients with trigger fingers averaged PROMIS scores among the other groups. Similar differences were observed in QuickDASH scores because patients with carpal tunnel syndrome and thumb arthritis reported clinically worse upper-extremity function than did patients with ganglion cysts and Dupuytren contracture. A strong correlation was seen between QuickDASH scores with both PROMIS Physical Function scores and Pain Interference scores. Conclusions: The PROMIS system is sufficiently able to capture differences in self-reported function and pain interference among patients with different hand conditions. Moreover, PROMIS Physical Function demonstrates construct validity when evaluated against a reference of the QuickDASH across nontrauma hand conditions. Clinical relevance: The use of PROMIS is expanding, but because PROMIS is not disease-specific, assessment of its construct validity is necessary for hand conditions.