Recent work has shown that screening for Hepatitis C is cost-effective from a societal perspective. Safety-net hospitals are committed to providing care for their many uninsured and underinsured patients who are unable to pay. Adopting a screening policy would commit the institution to pay for expensive treatment for many of the screened positives. OBJECTIVE: Examine the economic implications for a safety-net hospital that adopts a Hepatitis C screening policy. METHODS: A Markov decision analytic model was constructed, using a reference case of a 35 year-old male without symptoms of Hepatitis C. The perspective adopted was a safety-net hospital. Two populations were examined: uninsured, and insured, but without coverage for combination interferon+ribavirin. Screening consisted of ELISA followed by a confirmatory PCR. It was assumed that PCR and virus genotyping were sent to an outside laboratory. Data came from prior publications. Patients were considered to be patients of this facility for 5 years. RESULTS: In the uninsured group, screening costs an additional $245 per patient, with an incremental cost-effectiveness ratio(ICER) of $12,300/QALY. As prevalence of infection ranged from 0.8%-9%, the additional cost of screening ranged from $77-$587, and the ICER from $11,500/QALY-$16,800/QALY. In the underinsured group, screening was associated with an additional cost of $166 per patient, with an ICER of $8,300/QALY. Varying the prevalence produced additional costs of $38-$427. CONCLUSIONS: Although ICERs would appear to be cost-effective from a societal perspective, this is less clear for hospitals that deal with hard budgets, not the soft budget, cost-conscious environment assumed by incremental cost-effectiveness analysis. Screening for Hepatitis C may be an expensive policy to implement for safety-net hospitals. Public funding to support a screening and treatment program may be well justified.