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Background: Bronchoalveolar lavage (BAL) is indicated for medical evaluation of complex cases of lung disease. There is limited data on the performance of tuberculosis (TB) microbiologic tests on BAL in such patients, particularly in human immunodeficiency virus (HIV) and TB endemic areas. Methods: We evaluated the performance of Mycobacterium tuberculosis (Mtb) culture and up to two simultaneous Xpert MTB/RIF tests on BAL fluid against a consensus clinical diagnosis in 98 medically complex patients undergoing bronchoscopy over a two-year period in Durban, South Africa. Results: TB was the most frequently diagnosed lung disease, found in 19 of 98 participants (19%) and was microbiologically proven in 14 of these (74%); 9 (47%) were culture positive and 5 were positive on at least one Xpert MTB/RIF assay. Immunosuppression prevalence was high (26% HIV-infected, 29% on immunosuppressive therapy and 4% on chemotherapy). Xpert MTB/RIF had low sensitivity (45%) and high specificity (99%) when assessed against the consensus clinical diagnosis. Compared to TB culture, a single Xpert MTB/RIF increased the diagnostic yield by 11% and a second Xpert MTB/RIF by a further 16%. Conclusion: Although Xpert MTB/RIF had a low sensitivity, sending two tests improved the microbiologically-proven diagnostic yield of bronchoscopy from 47% to 74% compared to culture alone.