OBJECTIVES: Flu-like symptoms (pyrexia, chills, myalgia and arthralgia) are experienced by 30%-50% of chronic hepatitis C (CHC) patients undergoing combination interferon and ribavirin (RBV) treatment and are often cited as reasons for discontinuation. To track these symptoms, the Hepatitis Physical Symptom Severity Diary (HPSS-D), was developed. METHODS: Four items from the HPSS-D comprise the Flu-Like Symptom Index (Index): fever, chills, muscle aches/pain, and joint pain. Response options ranged from 0 (no symptoms) to 10 (worst symptom/problem) over the past 24 hours. The diary was completed for 7 consecutive days at baseline and weeks 4, 8 and 12. Data from two Phase 2b studies of treatment-naïve patients comparing pegIFNalpha2a/RBV (peg-alfa) to peg-INF Lambda/RBV (peg-lambda) and peg-alfa to peg-alfa and direct acting antiviral were combined. Measurement properties were assessed. Mean and change scores and proportions of patients reporting flu-like symptoms were calculated. RESULTS: Measurement properties of the Index were supported with test-retest ICC value of 0.85, Cronbach’s alpha range: 0.73-0.81, low to moderate construct validity [range: 0.23-0.63], and demonstrated known groups validity (based on physician-reported flu symptoms). Responsiveness coefficients suggested a small to medium effect (SES=0.40;SRM=0.39). MIDs were 2.5-3.0 points. Mean Index scores at week 12 for the peg-alfa group (N=36) increased from baseline by 2.39 ± 4.95 versus 0.83 ± 5.05 for peg-lambda patients (N=26). The percentage reporting any flu-like symptoms was significantly higher for peg-alfa (75%) versus peg-lambda patients (27%) at week 12, (p<0.001), despite similar baseline rates. Fewer peg-lambda versus peg-alfa patients (50% versus 82%) experienced clinically significant worsening of flu-like symptoms. CONCLUSIONS: PRO measures are important parameters to gauge patients’ experience with treatment, providing systematic assessment of treatment benefit and side effects. This new Flu-Like Symptom Index from the HPSS-D demonstrated adequate measurement properties and detected lower intensity and frequency of flu-like symptoms for peg-lambda versus peg-alfa patients.