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The phenotypic impact on etravirine susceptibility was examined in plasma specimens from 40 nonnucleoside reverse transcriptase inhibitor-experienced HIV patients with distinct nonnucleoside reverse transcriptase inhibitor resistance-associated mutations. Some etravirine resistance-associated mutations produced larger reductions in fold change than others. Y181C in combination with at least one etravirine resistance-associated mutation caused, on average, a 12.6-fold reduced susceptibility to etravirine. Two novel changes, K101H and E399D, significantly diminished etravirine susceptibility. Thus, the original etravirine resistance-associated mutation list should be updated and weighted for a suitable genotypic resistance interpretation.