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Background. Nevirapine (NVP) can be safely and effectively administered once-daily but has not been assessed in human immunodeficiency virus (HIV)–infected patients with tuberculosis (TB). We studied the safety and efficacy of once-daily NVP, compared with efavirenz (EFV; standard therapy); both drugs were administered in combination with 2 nucleoside reverse-transcriptase inhibitors.Methods. An open-label, noninferiority, randomized controlled clinical trial was conducted at 3 sites in southern India. HIV-infected patients with TB were treated with a standard short-course anti-TB regimen (2EHRZ3/4RH3; [2 months of Ethambutol, Isoniazid, Rifampicin, Pyrazinamide / 4 months of Isoniazid and Rifampicin] thrice weekly) and randomized to receive once-daily EFV at a dose of 600 mg or NVP at a dose of 400 mg (after 14 days of 200 mg administered once daily) with didanosine 250/400 mg and lamivudine 300 mg after 2 months. Sputum smears and mycobacterial cultures were performed every month. CD4+ cell count, viral load, and liver function test results were monitored periodically. Primary outcome was a composite of death, virological failure, default, or serious adverse event (SAE) at 24 weeks. Both intent-to-treat and per protocol analyses were done, and planned interim analyses were performed.Results. A total of 116 patients (75% [87 patients] of whom had pulmonary TB), with a mean age of 36 years, a median CD4+ cell count of 84 cells/mm3, and a median viral load of 310 000 copies/mL, were randomized. At 24 weeks, 50 of 59 patients in the EFV group and 37 of 57 patients in the NVP group had virological suppression (P = .024). There were no deaths, 1 SAE, and 5 treatment failures in the EFV arm, compared with 5 deaths, 2 SAEs, and 10 treatment failures in the NVP arm. The trial was halted by the data and safety monitoring board at the second interim analysis. Favorable TB treatment outcomes were observed in 93% of the patients in the EFV arm and 84% of the patients in the NVP arm (P = .058).Conclusions. Compared with a regimen of didanosine, lamivudine, and EFV, a regimen of once-daily didanosine, lamivudine, and NVP was inferior and was associated with more frequent virologic failure and death.Clinical Trials Registration. NCT00332306.