A new paradigm for the treatment of pulmonary tuberculosis: the use of combination therapy in the first 2 months. This commentary considers the available evidence about the clinical course and management of tuberculosis during the first 2 months of treatment. Recent data show that patients with drug-susceptible tuberculosis who receive a standardized combination regimen (isoniazid, rifampin, pyrazinamide, and ethambutol) in the first 2 months of therapy (HRZE) have a low risk of relapse, are cured, and have only a low risk of adverse events (death, treatment failure, or relapse). In addition, the data indicate that patients who have drug-susceptible tuberculosis are at high risk of early adverse events if they are untreated, which should be considered before starting treatment. Among patients treated with HRZE, the rate of culture conversion and the drug levels are important determinants of the probability of relapse. We present two management algorithms for patients with tuberculosis, based on the available evidence. The first is for patients with tuberculosis who receive directly observed therapy for 2 months (2 mo), the other for patients treated in the context of directly observed therapy of unknown duration (unknown duration). We provide some guidance to clinicians on their use of these algorithms in daily practice.