This study describes an early bactericidal activity (EBA) study investigating the optimal dose of isoniazid (INH) for patients with INH-resistant tuberculosis mediated by inhA mutations.They reexamine the measures of sputum bacterial load used with regard to the presence of drug resistance-conferring mutations.The parent study, AIDS Clin. Trials Group A5312, is an ongoing phase 2A, open-label trial in which individuals with smear- pos. pulmonary tuberculosis with INH resistance mediated by inhA mutation were randomized to receive INH at 5, 10, or 15 mg/kg daily for 7 days.Of 59 participants enrolled, 43 participants (73%) had mycobacteria with inhA mutations at least and thirty-one participants (52%) had mycobacteria with addnl. mutations conferring rifampicin resistance, three participants (5%) had mycobacteria with mutations conferring fluoroquinolone resistance, and one participant (2%) had mycobacteria with mutations conferring aminoglycoside resistance.Mutations were detected by line probes only, thus not allowing quantification of proportions of mutated bacilli and varying degrees of fitness cost or compensatory effects.Mutations were detected by line probes only, thus not allowing quantification of proportions of mutated bacilli and varying degrees of fitness cost or compensatory effects. Larger cross-sectional studies including whole-genome sequencing to detect a broader diversity of strains, mutations, and subpopulations is needed to investigate this further.