Recommendations on the management of smear-negative pulmonary tuberculosis (TB) are still based on the behaviour of this disease in populations unaffected by the human immunodeficiency virus (HIV). Studies prior to the HIV epidemic estimated that there were 1.22 cases of smear-negative and extra-pulmonary TB for each smear-positive case. Patients with smear-negative pulmonary TB were found to be less infectious and to have a lower mortality, but a significant proportion (50%-71%) progressed to active disease justifying treatment. Moreover, a wide variety of regimens also proved effective in the treatment of smear-negative disease in HIV-negative patients. The advent of HIV has changed many of these parameters. Countries affected by both HIV and TB have experienced a disproportionate increase in smear-negative disease. While apparently remaining less infectious than smear-positive cases, HIV-positive patients with smear-negative pulmonary TB are generally more immunocompromised, have more adverse drug reactions, and suffer higher mortality rates on treatment. Clinical decision-making has also been complicated because HIV co-infection broadens the differential diagnoses of smear-negative pulmonary TB to include diseases such as Pneumocystis carinii pneumonia (PCP), pulmonary Kaposi's sarcoma, and Gram-negative bacteraemia. Our approach to smear-negative pulmonary TB must therefore adapt to these changed parameters. Management algorithms based on several features (clinical symptoms, response to antibiotic trials, smear investigations, and chest radiography) have been developed to improve case detection. These algorithms must be validated in each locale because their performance will vary depending on numerous local factors such as the regional prevalence of PCP. Alternative methods of specimen collection, such as sputum induction, and processing must be evaluated. National tuberculosis programmes should also consider extending the use of rifampicin-based short-course chemotherapy (SCC) to new patients with smear-negative disease. This latter intervention, and the much-needed establishment of additional microscopy and culture facilities, will depend on increased financial and technical support from the international community.