Because there is no tuberculin screening schedule currently recommended for adults, we used a Markov process in a cost-effectiveness analysis to determine an optimal strategy. We simulated the prognosis of a cohort of black 20-year-olds to evaluate the effects of various screening schedules with intradermal tuberculin and administration of isoniazid prophylaxis to those with positive results. The schedule with the lowest cost-effectiveness ratio is a single screening at 50 years of age, which costs $41,672 per quality-adjusted life year (QALY) gained. The cost-effectiveness ratio is nearly the same for all schedules involving a single screening between 30 and 70 years of age. Repeated screening strategies are less cost effective. Sensitivity analysis shows that the range of acceptable screening strategies changes significantly under alternate assumptions about the mortality from isoniazid hepatitis. However, screening at 50 years of age remains nearly optimal under the alternatives considered. Altering the values of other parameters generally produced only small changes. Tuberculin screening at 50 years of age should be added to primary care preventive practices because the strategy is as cost effective as standard health interventions and is robust to alternative assumptions. If further research confirms the base case assumptions about isoniazid toxicity, consideration should be given to increasing screening to every 10 years, which would produce a larger health benefit, albeit at substantially higher cost.