BACKGROUND Previous decision analyses of isoniazid preventive therapy for low-risk tuberculin reactors aged 20 to 34 years have not accounted for the recently increased isoniazid resistance rate. Drug resistance trends could also affect the decision to use isoniazid preventive therapy for patients with recent conversion of tuberculin skin tests who are seronegative for human immunodeficiency virus. METHODS A decision analysis was performed with a Markov simulation to assess the difference in life expectancy between those who receive isoniazid preventive therapy and those who do not. Probability estimates were determined from a review of the literature. RESULTS For tuberculin reactors aged 20 to 34 years living in areas with 26% isoniazid resistance, isoniazid preventive therapy increases life expectancy by 2 days. Withholding isoniazid is clearly favored if the isoniazid hepatitis rate is 1.1% and the hepatitis fatality rate exceeds 2.8%. For recent tuberculin converters, isoniazid preventive therapy increases life expectancy by 14 to 17 days, depending on patient age. Withholding isoniazid from converters is favored only if the isoniazid resistance rate exceeds 90% to 98%, according to patient age. Two-way sensitivity analysis of isoniazid-associated hepatitis and hepatitis-related fatality rate did not affect the decision to use isoniazid for recent converters. CONCLUSIONS For tuberculin reactors aged 20 to 34 years who are seronegative for human immunodeficiency virus and living in areas with high isoniazid resistance, there is minimal net benefit of isoniazid preventive therapy. The current recommendation to provide isoniazid preventive therapy to this patient population should be reexamined. For recent tuberculin converters aged 20 to 64 years who are seronegative for human immunodeficiency virus, isoniazid preventive therapy provides a small increase in life expectancy. Withholding isoniazid preventive therapy for human immunodeficiency virus-seronegative skin test converters at high risk for isoniazid-induced hepatitis may be considered; preventive therapy is advisable for all other recent converters.