In 1997, there were approximately eight million new active cases of tuberculosis but only two percent of cases were in established market economies. There is a need for new drugs that could shorten treatment times but a concern about return on investment (ROI) in this disease area. OBJECTIVE: To measure the ROI for a tuberculosis drug development program. METHODS: ROI may be measured by computing the net present value of the estimated costs and revenue streams. An EXCEL spreadsheet model was prepared that had a 25- year time horizon, starting as the molecule entered Phase 1 trials. The model included costs for clinical trials, non-clinical development, manufacturing development, cost of goods, and sales and marketing. Revenues were estimated for each year after launch assuming three years to peak sales, five years at peak sales, and a 20 year patent life from the start of Phase 1. A discount rate of 12 percent was used to compute the net present value. Alternative cost scenario models were based on whether time from start of Phase 1 to launch was 10 years (normal) or seven years (rapid) and whether clinical trials were conducted in the US or Uganda. Alternative revenue scenarios were also modeled. RESULTS: Total discounted costs were $13.9 million, $21.3 million, $9.0 million, and $13.7 million for the normal US, rapid US, normal Uganda, and rapid Uganda scenarios and medium revenue stream. Total discounted revenue for the medium revenue assumption was $28.0 million at normal development and $46.6 million at rapid development. Net present values ranged between $6.8 million and $162.1 million for the 12 combinations of costs and revenues modeled. CONCLUSIONS: Drugs for tuberculosis will have a positive return on investment if molecules can be identified when they enter Phase 1 of development.