Background. Hepatitis B virus (HBV) continues to cause significant morbidity and mortality in the United States. Current guidelines suggest screening populations with a prevalence ofR2%. Our objective was to determine whether this screening threshold is cost-effective and whether screening lower-prevalence populations might also be cost-effective. Methods. We developed a Markov state transition model to examine screening of symptomatic outpatients in the United States. The base case was a 35-year-old man living in a region with an HBV infection prevalence of 2%. Interventions (versus no screening) included screening for Hepatitis B surface antigen followed by treatment of appropriate patients with (1) pegylated interferon-a2a for 48 weeks, (2) a low-cost nucleoside or nucleotide agent with a high rate of developing viral resistance for 48 weeks, (3) prolonged treatment with low-cost, high-resistance nucleoside or nucleotide, or (4) prolonged treatment with a high-cost nucleoside or nucleotide with a low rate of developing viral resistance. Effectiveness was measured in quality-adjusted life years (QALYs) and costs in 2008 US dollars. Results. Screening followed by treatment with a low-cost, high-resistance nucleoside or nucleotide was costeffective ($29,230 per QALY). Sensitivity analyses revealed that screening costs ,$50,000 per QALY in extremely low-risk populations unless the prevalence of chronic HBV infection is ,.3%. Conclusions. The 2% threshold for prevalence of chronic HBV infection in current Centers for Disease Control and Prevention/US Public Health Service screening guidelines is cost-effective. Furthermore, screening of adults in the United States in lower-prevalence populations (eg, as low as .3%) also is likely to be cost-effective, suggesting that current health policy should be reconsidered.