We evaluated the sensitivity and specificity of the WHO immunological criteria for detecting antiretroviral therapy (ART) treatment failure in a cohort of Vietnamese patients. We conducted a stratified analysis to determine the effects of BMI, peer support, adherence to antiretroviral (ARV) drugs, age, and gender on the sensitivity and specificity of the WHO criteria. We conducted a retrospective cohort study of 605 HIV-infected patients using data previously collected from a cluster randomized control trial study. We compared the sensitivity and specificity of CD4+ counts to the gold standard of virologic testing as a diagnostic test for ART failure at different time points of 12, 18, and 24 months. The sensitivity 95% confidence interval (CI) of the WHO immunological criteria based on a viral load ≥ 1000 copies/mL was 12% (5%-23%), 14% (2%-43%), and 12.5% (2%-38%) at 12, 18, and 24 months, respectively. In the same order, the specificity was 93% (90%-96%), 98% (96%-99%), and 98% (96%-100%). The positive predictive values (PPV) at 12, 18, and 24 months were 22% (9%-40%), 20% (3%-56%), and 29% (4%-71%); the negative predictive values (NPV) at the same time points were 87% (84%-90%), 97% (95%-98%), and 96% (93%-98%). The stratified analysis revealed similar sensitivities and specificities. The sensitivity of the WHO immunological criteria is poor, but the specificity is high. Although testing costs may increase, we recommend that Vietnam and other similar settings adopt viral load testing as the principal method for determining ART failure.