OBJECTIVES: The Food and Drug Administration’s (FDA) clinical trial guidelines for development of patient reported outcome (PRO) instruments recommends deriving the PRO concepts from the target population using qualitative research. Since the PRO instruments currently used in clinical trials of hepatitis C (HCV) patients are not developed specifically for this patient population, the FDA’s recommendation is not fulfilled. The purpose of this study was to identify a comprehensive list of health related quality of life (HRQoL) themes that may be unique to HCV by reviewing qualitative studies of HCV patients. METHODS: Ovid Medline, Ovid Embase, Ovid PsycINFO, and PubMed were searched for peer-reviewed journals from 1946 to 2012. Inclusion criteria required primary studies to include HCV patients; be published in English; and used qualitative methods to report an aspect of the HCV experience. Studies were excluded if secondary data was used or there were proxy views. Included studies were graded on study quality using the Qualitative Assessment and Review Instrument.  Eligible studies were then analyzed using meta-synthesis; findings from individual studies were grouped into themes which were combined to generate HRQoL domains. RESULTS: Ten studies met the inclusion/exclusion criteria and the quality assessment criteria and were included for review. Eleven themes were identified: physical symptoms, physical activities, guilt, stigma, emotional distress, psychological behavior, social relationship, social activities, work function, sexual function, and cognitive function. The type of themes identified in each study varied by the focus of the primary study and the analytical framework used in the qualitative studies. The themes were further grouped into six HRQoL domains: physical, psychological/emotional, social, work, sexual, and cognitive functionality. CONCLUSIONS: The systematic review represents a useful starting point in the critical appraisal of the PRO instruments used for clinical trials in HCV patients.