OBJECTIVES:  Patients with Clostridium difficileinfection (CDI) can experience long-term symptoms that resemble a chronic disease state.  Despite this, a health-related quality of life (HRQOL) instrument specific for patients with CDI does not exist. The goal of this study was to develop and validate a disease specific instrument to assess HRQOL in patients with CDI. METHODS: A systematic literature review was conducted to identify HRQOL instruments and questions related to general health (n=3) or gastrointestinal disease (n=13) related to CDI HRQOL.  Removing duplicate questions and using direct patient (n=10) or clinician (n=10) interviews, a 36-item survey specific to CDI HRQOL was developed.  Test-retest and acceptability of item selection was tested on 20 CDI patients and 20 healthy volunteers.  The Cdiff36 HRQOL survey was then tested using 100 patients with CDI and compared to the RAND Short-Form 36 (SF-36) Health Survey.  Domains containing questions with a correlation coefficient of >0.7 were considered acceptable.  To compare population average scores for patients with CDI, the SF-36 was also administered to 82 patients given broad-spectrum antibiotics. RESULTS: SF-36 scores were significantly higher in healthy controls (72±22) compared to patients on broad-spectrum antibiotics (54±12) or patients with CDI (43±17); p<0.05 each vs. control.  The final version of the Cdiff36 contained six domains: daily activities (4 items), anxiety (3 items), diet (3 items), sleep (2 items), discomfort (6 items), health perception (6 items), dysphoria (6 items), relationship (2 items), and social interaction (3 items).  CDiff36 scores correlated significantly based on recurrence vs. primary CDI as well as time since last episode (p<0.05, each).  Cdiff36 scales also correlated significantly with the SF-36. CONCLUSIONS: The properties of the Cdiff36 should make it appropriate to assess changes over time in HRQOL in patients with CDI.  Future language translations and validation will be required for global use of the CDiff36.