There are limited data on transmitted antiretroviral resistance in young children who require antiretroviral therapy. We adapted the World Health Organization surveillance strategy, testing antiretroviral naive infants (<18 months) in the Western Cape Province of South Africa, and detecting only 3 non-nucleoside reverse transcriptase inhibitors (NNRTI) and no NRTI or protease inhibitor surveillance mutations in 49 patients. The estimated NRTI and protease inhibitor transmitted antiretroviral resistance prevalence is low (<5%), predicting good therapeutic response in Western Cape infants.