Objective:To assess the economic benefits and costs of providing isoniazid preventive therapy for tuberculosis (TB) in HIV-infected persons in Zambia.Design:A spreadsheet model incorporating variables drawn from published studies and unpublished data.Subjects:Data drawn from a number of different studies and published literature involving a range of subjects.Setting:Zambia.Results:Using data primarily from Zambia we have modelled the costs and benefits of a TB preventive therapy programme using daily isoniazid for 6 months. The base-case scenario assumes recruitment at a voluntary testing and counselling site where HIV seroprevalence is 30%; persons with HIV have a 25% probability of developing active TB during their lifetime; two additional cases of TB would be prevented per person completing a course of preventive therapy; compliance would be 63%, and the efficacy of the isoniazid in preventing active TB of 60%. The costs under this scenario would exceed the benefits by a factor of 1.16 [benefit: cost ratio (BCR) of 0.86]. However, if preventing one case of TB prevented an additional five cases, the benefits would exceed the costs by a significant margin (BCR of 1.71). Other scenarios indicate that the targeted preventive therapy of persons with HIV whose occupation or living situation places them in contact with a large number of others (teachers and students, health personnel, military and police, miners, prisoners, etc.) would yield significant net benefits. The operational challenge for TB preventive therapy is thus to identify and target large numbers of such persons.