Objective: Diarrhea without infectious etiology (episodic, chronic) is reported in excess of 20% of HIV/AIDS patients receiving standard of care HAART therapy. Diarrhea of any severity and/or frequency negatively affects health-related quality of life (HRQoL) for these individuals. No instrument specific to the impact of HIV/AIDS-related diarrhea currently exists. To measure a HRQoL benefit from a new oral antidiarrheal in clinical testing, a new PRO instrument is being developed. Methods: Comprehensive review of the HRQoL literature of diarrhea in the general and HIV/AIDS populations was conducted and experts in HIV and GI medicine were interviewed. Focus groups of HIV+ individuals experiencing diarrhea were undertaken. The psychometric properties of the draft questionnaire items were evaluated from data collected via the Internet in 320 respondents. Also collected within the cross-sectional, development study were respondent demographics, bowel movement history, SF-12, and Work Productivity & Activity Impairment (WPAI) questionnaire. Following item reduction, content validity was evaluated by cognitive debriefing. Results: Literature review, expert feedback, and focus groups informed the conceptual model and construction of 41 draft questions regarding HRQoL related to chronic diarrhea among HIV+ individuals. Item reduction was achieved by exploratory and confirmatory factor analyses and confirmed a one-factor best fit model. A generalized, partial credit IRT analysis facilitated further item reduction. Differential item functioning analyses confirmed no significant differences in item performance among subgroups tested. Convergent and discriminate validity were supported by correlations with SF-12 scales, WPAI and self-reported symptom frequency and severity scores (correlation coefficients 0.58 to 0.71), and analysis of variance among clinically defined diarrhea severity (F=32, p <0.0001, ç2 0.17). Conclusion: A newly developed survey assessing the impact of chronic diarrhea on HIV+ patients has demonstrated acceptable psychometric properties. The survey will be validated in a double-blind, placebo-controlled diarrhea treatment study.