OBJECTIVES: Recent advances in treatment for chronic hepatitis C (CHC) virus infection have shortened duration of treatment and increased the likelihood of treatment success.  To understand what unmet needs remain with available CHC treatments, patient interviews explored what it is like to live with CHC infection and undergo CHC treatment. A subset of interviews also evaluated the content validity and comprehension of patient-reported outcome (PRO) questionnaires for use in CHC clinical trials. METHODS: Sixty-five patients with clinician-confirmed diagnosis of CHC infection provided informed consent and completed interviews in Germany (n=15), France (n=15), the USA (n=16), and Canada (n=19).  Targeted sampling enrolled a demographically and clinically diverse sample.  Concept elicitation (CE) interviews (n=58) using in-depth, open-ended questioning encouraged spontaneous discussion of patients’ experience of CHC and its treatment.  Patients in the USA and Canada also completed cognitive debriefing (CD) interviews using a ‘think aloud’ protocol to evaluate content validity and comprehension of the Fatigue Severity Scale (FSS, n=34), Work Productivity and Activity Impairment questionnaire for Hepatitis C (WPAI:Hepatitis C, n=7) and the SKINDEX-16 (n=12). Verbatim transcripts were translated to English and analyzed using thematic analysis.   RESULTS: Treatment-related symptoms cause a significant burden for patients during treatment with tiredness (60.0%), sleep problems (57.5%), fatigue (50.0%), depression (45.0%) and itchy skin (40.0%) among the most commonly reported symptoms mentioned in CE interviews.  In the 40 patients with CHC treatment experience, treatment-related symptoms led to discontinuation or lack of adherence in 25% and 10%, respectively.  CD interviews confirmed that the questionnaires were relevant, understandable and easy to complete. Patients suggested minor wording changes that may make these questionnaires easier to complete. CONCLUSIONS: Treatment-related symptoms cause a significant burden for CHC patients and affect their adherence to treatment. The FSS, WPAI:Hepatitis C, and SKINDEX-16 are valid tools for PRO assessment in CHC clinical trials.