The study documents the frequency of nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor mutations that are prevalent in the first-line failing HIV-infected patients of South Indian region and adds up to the data for developing future algorithms to study the drug-resistance mutations of HIV subtype C. Thus, the results of the study call for the need for rational approach for selecting and for frequent viral monitoring to be performed to detect failure, followed by genotyping.