BACKGROUND: Several anti-viral treatments are now available for HBeAg-negative chronic hepatitis B (CHB), but the clinical and economic outcomes of potential treatment strategies and durations are unclear. AIM: To examine the clinical and economic outcomes of potential treatment strategies and durations for HBeAg-negative CHB. METHODS: We conducted a cost-utility analysis from a payer perspective over a lifetime time horizon. Disease progression probabilities, costs and quality of life data were derived from the literature. We evaluated 5-year, 10-year, lifetime and 5 on-1 off treatment durations. For each of these treatment durations, we evaluated initial therapy with entecavir, lamivudine or adefovir, with addition of adefovir or entecavir for patients who developed virological breakthrough because of resistance (12 strategies total). RESULTS: Increasing treatment duration improved quality-adjusted life-years (QALYs) and was generally cost-effective for all three drugs. However, a 5 on-1 off strategy was the most cost-effective: lifetime vs. 5 on-1 off entecavir had an ICER of $148,200/QALY. In probabilistic sensitivity analyses, entecavir 5 on-1 off was the preferred strategy over the range of commonly reimbursed cost-effectiveness thresholds. Lifetime treatment was preferred to a 5 on-1 off strategy, if treatment durability was < 10%. CONCLUSION: The results of our analysis suggest that in HBeAg-negative CHB infection, a 5 on-1 off treatment strategy with entecavir improves health outcomes in a cost-effective manner compared to alternative strategies.