This study examined whether costs associated with tuberculosis (TB) screening and directly observed preventive therapy (DOPT) among drug injectors attending a syringe exchange are justified by cases and costs of active TB cases prevented and examined the impact of monetary incentives to promote adherence on cost-effectiveness. We examined program costs and projected savings using observed adherence and prevalence rates and literature estimates of isoniazid (INH) preventive therapy efficacy, expected INH hepatoxicity rates, and TB treatment costs; we conducted sensitivity analyses for a range of INH effectiveness, chest X-ray (CXR) referral adherence, and different strategies regarding anergy among persons affected with human immunodeficiency virus (HIV). For 1,000 patients offered screening, incorporating real observed program adherence rates, the program would avert $179,934 in TB treatment costs, for a net savings of $123,081. Assuming a modest risk of TB among HIV-infected anergic persons, all strategies with regard to anergy were cost saving, and the strategy of not screening for anergy and not providing DOPT to HIV-infected anergic persons resulted in the greatest cost savings. If an incentive of $25 per person increased CXR adherence from the observed 31% to 50% or 100%, over a 5-year follow-up the net cost savings would increase to $170,054 and $414,856, respectively. In this model, TB screening and DOPT at a syringe exchange is a cost-effective intervention and is cost-saving compared to costs of treating active TB cases that would have occurred in the absence of the intervention. This model is useful in evaluating the cost impact of planned program refinements, which can then be tested. Monetary incentives for those referred for screening CXRs would be justified on a cost basis if they had even a modest beneficial impact on adherence.