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Objectives: To determine the main causes of acid-fast bacillus sputum smear-negative pneumonia in Asian and African HIV-infected patients, Design and Setting: A prospective multicenter study (ANRS 1260) of consecutive hospitalized patients in tertiary hospitals in Phnom Penh, Ho Chi Minh City, Bangui and Dakar., Intervention: Use of the same clinical, radiological and biological methods at the four sites; regular quality controls of participating laboratories; final review of medical records by experts. Similar criteria used to establish diagnoses., Results: In all 462 patients were enrolled, 291 in Asia and 171 in Africa. The median CD4 cell count was 25 cells/microl. Radiological opacities were diffuse in 42% of patients and localized in 45%. Fiberoptic bronchoscopy was performed in 354 patients, at similar rates in the four sites. A definite and/or probable diagnosis was obtained in 375 patients (81%). Pneumocystis jiroveci pneumonia, bacterial pneumonia, AFB sputum smear-negative tuberculosis and other infections (fungi, parasites, atypical mycobacteria) were diagnosed in respectively 47, 30, 17 and 12% of Asian patients and 3, 48, 26 and 5% of African patients., Conclusion: In South-east Asia, acid-fast bacillus smear-negative pneumonia is caused by a wide variety of pathogens. When possible, fiberoptic bronchoscopy must be performed rapidly if clinical data are not highly suggestive of bacterial pneumonia, Pneumocystis jiroveci pneumonia or tuberculosis. In contrast, in Africa, bacterial pneumonia and tuberculosis are responsible for the large majority of cases. Fiberoptic bronchoscopy should be restricted to patients with clinical and/or radiological findings not suggestive of bacterial pneumonia or tuberculosis, antibiotic failure, and three consecutive negative sputum smears.