Tenofovir disoproxil fumarate (tenofovir DF) is a prodrug of tenofovir, a nucleotide reverse transcriptase inhibitor. In two large, well designed, placebo-controlled clinical trials, tenofovir DF 300 mg/day resulted in significant reductions in HIV-1 RNA from baseline compared with placebo at 24 weeks in antiretroviral-experienced patients with HIV infection. Patients in both treatment groups continued to receive existing stable antiretroviral therapy. In an extension phase of one trial, these reductions in viral load were maintained after 96 weeks of treatment with tenofovir DF. Preliminary data from a large, 3-year comparative trial suggest the clinical efficacy of tenofovir DF in combination with baseline antiretroviral therapy is similar to that of stavudine in antiretroviral-naive patients with HIV infection. Virological substudies showed that viral suppression was maintained in patients who developed new reverse transcriptase mutations during tenofovir DF therapy (in combination with existing stable antiretroviral drugs) for up to 48 weeks. Isolates of HIV infrequently developed the K65R mutation during 96 weeks of tenofovir DF therapy. Tenofovir DF is generally well tolerated. The most commonly observed adverse events seen with tenofovir DF (in combination with other antiretroviral drugs) were predominantly of a gastrointestinal nature.