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To evaluate the virologic responses and mutational profiles in antiretroviral-experienced patients adding tenofovir DF once-daily to their existing regimens.Resistance analyses were performed for patients in a phase II placebo-controlled clinical trial of tenofovir DF.HIV-1 reverse transcriptase and protease genes from plasma samples were analyzed genotypically and phenotypically at baseline, week 24, and week 48.Of 184 patients, 173 (94%) had baseline HIV-1 expressing one or more nucleoside reverse transcriptase inhibitor-associated resistance mutation. Protease inhibitor and non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations were observed in 57% and 32% of patients, respectively. Compared to placebo, significant reductions in HIV-1 RNA were observed for tenofovir DF-treated patients who had thymidine analog- (TAM), lamivudine- (M184V), NNRTI- or protease inhibitor-associated mutations. Patients with phenotypic susceptibility to tenofovir within 4-fold of wild-type responded durably to tenofovir DF 300 mg therapy with a decline in plasma HIV-1 RNA of ≥ 0.5 log10 copies/ml; few patients had a more than 4-fold reduced susceptibility to tenofovir at baseline. Four patients (2%) developed the K65R mutation (selected by tenofovir in vitro) and showed 3- to 4-fold reductions in tenofovir susceptibility but no evidence of rebound viremia. Thirty-four percent of patients developed additional TAMs, coincident with concurrent zidovudine or stavudine therapy, but also showed durable HIV-1 reductions. There was no evidence of novel resistance to tenofovir.Adding tenofovir DF 300 mg to an existing regimen in patients with ongoing viral replication and a wide range of genotypic resistance patterns resulted in significant and durable HIV-1 RNA reductions. In addition, there was a low incidence of genotypic or phenotypic resistance to tenofovir DF arising during 48 weeks of therapy.