OBJECTIVES: New protease inhibitors (PIs) significantly improve sustained virological responses (SVRs) in patients with genotype 1 chronic hepatitis C. However, treatment (Tx) in prior null-responders with advanced fibrosis often results in failure to achieve SVR and development of resistant mutations.  Emerging quadruple Tx adding two direct antiviral agents may achieve SVR in nearly all of these patients. This study aimed to compare two strategies: 1) treating prior null-responders with fibrosis stage 3 (F3) or stage 4 (F4) with telaprevir + peginterferon + ribavirin (“T+P+R strategy”) versus 2) withholding Tx until more effective antiviral agents become available (“Wait strategy”).  METHODS: The MONARCH Hepatitis C cost-effectiveness model was used to project outcomes in cohorts of 55-year-old prior null-responders using published dynamic transition rates for disease progression. “T+P+R strategy” achieves SVR in 42% of F3 and in 14% of F4 patients. In the Wait strategy, patients would wait for 5 years and then initiate quadruple Tx yielding 90% SVR. Quadruple Tx would be used as rescue in patients failing “T+P+R”, 70% of whom would harbor virus resistant to PIs. Patient outcome in terms of SVR and quality-adjusted-life years (QALYs) were assessed 10 years thereafter. Benefits were discounted at 3.5%. RESULTS: Projected SVR rates were higher with the “Wait strategy” (76% and 65% for F3 and F4 respectively) than “T+P+R strategy” (50% and 30% for F3 and F4 respectively). Per-patient expected QALYs were higher for “Wait strategy” than “T+P+R strategy”; 8.59 versus 8.47 QALYs in F3 patients and 7.5 versus 6.7 QALYs in F4 patients. The "Wait strategy" was associated with one-third fewer re-treatments. CONCLUSIONS: Waiting for future quadruple antiviral therapy maximized the predicted health benefit both in terms of response (SVR) and QALYs; furthermore, the reduction in re-treatments associated with the "Wait strategy" is noteworthy given the likely high cost of triple therapy.