Studies have suggested that the Mycobacterium tuberculosis Beijing genotype causes more severe clinical disease and higher treatment failure rates with standard regimens, possibly in association with an increased risk of acquiring drug resistance. We studied the effect of genotype on treatment failure in a rural area in Vietnam where multidrug resistance is strongly associated with the Beijing genotype.In a population-based prospective cohort study, patients with smear-positive tuberculosis were tested before and after treatment by spoligotyping and drug susceptibility analysis. Reinfections were excluded by DNA fingerprinting. The outcome was treatment failure based on culture.Of 1106 patients eligible for analysis, 33 experienced treatment failure (3.0%; 95% confidence interval [CI], 2.1%-4.1%). The proportion of failure was 5.3% (95% CI, 0.3%-7.9%) among 380 patients with Beijing genotype infections. Multidrug-resistant tuberculosis strongly predicted failure (odds ratio [OR], 114; 95% CI, 30-430). After adjusting for multidrug-resistant tuberculosis, treatment failure was not associated with the Beijing genotype (adjusted OR, 0.7; 95% CI, 0.3-2.0). Amplification of drug resistance occurred in 3 patients (0.3%; 95% CI, 0.1%-0.7%) and was associated with multidrug resistance at baseline (P = .004) but not with the Beijing genotype. No multidrug resistance was created.The Beijing genotype was not associated with treatment failure in Vietnam; apparent associations were explained by the strong association of this genotype with multidrug resistance. Amplification of resistance in this patient population was rare.