OBJECTIVES: The Patient-Reported Outcome Measurement Information System (PROMIS), funded by the National Institute of Health (NIH) is a large database of precise measures of patient-reported health status for physical, mental, and social well-being.  Use of the PROMIS tools to evaluate humanistic outcomes in hospitalized patients with Clostridium difficile infection (CDI) has not been studied.  The objective of this study was to identify and validate the use of specific PROMIS network questions to evaluate patient-reported health status associated with CDI.  METHODS: This was a prospective, observational, two-center, mixed-methods study. Hospitalized adult patients with CDI were interviewed within seven days of a positive toxin test for C. difficile and again within one week of hospital discharge (N = 40).  Patients were asked open-ended questions regarding their top three concerns related to CDI.  Results were analyzed using ATLAS.ti 7 and classified by PROMIS domains.  Based on response trends, applicable standardized questions from the PROMIS network were identified.  An additional 15 patients with CDI were interviewed using the PROMIS questions to validate relevant questions. RESULTS: Patient reported humanistic outcomes within seven days of CDI diagnosis were primarily associated with mental concerns (75%) related to anxiety and worry about future complications. Physical concerns (8%) were related to ongoing diarrhea, bowel incontinence and other abdominal complaints.  Social concerns (3%) included interference with daily living and finances.  Patient reported outcome responses did not change significantly during the follow-up interview.  Using these responses from direct interviews of CDI patients, 18 PROMIS network questions were identified and demonstrated evidence of reliability. CONCLUSIONS: Using the NIH PROMIS network, we identified 18 patient-reported health status questions that can be used to evaluate humanistic outcomes in patients with CDI. Future studies should use these questions to assess changes in health status of CDI patients over time.