Forty-five human immunodeficiency virus (HIV)-infected patients stopped taking treatment but resumed taking it thereafter. All 11 who resumed treatment with their prior protease inhibitor (PI)-based regimen reattained an undetectable virus load, whereas this occurred for only 15 (44%) of 34 patients who resumed nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based treatment (P<.001). Distinct pharmacokinetics and resistance barriers may result in different performances for PIs and NNRTIs after treatment interruptions.