OBJECTIVE To assess the efficacy of tenofovir disoproxil fumarate (TDF) monotherapy by following the initial rate of decline in plasma viral load, which is a measure of the efficacy of therapy in blocking viral replication. DESIGN An open-label, single-site study of TDF monotherapy in 10 antiretroviral drug-naive chronically HIV-1-infected individuals. METHODS Antiviral responses were assessed at baseline and during 21 days of monotherapy with TDF by measuring plasma HIV-1 RNA levels. The rate of change in HIV-1 RNA from baseline was determined both by linear regression and by fitting to a published model. Slopes were compared with those previously determined for ritonavir monotherapy. RESULTS Over 21 days, mean plasma HIV-1 RNA levels in the TDF-treated patients fell 1.5 log(10) copies/ml (range, 0.7-2.0). The initial rates of decline in plasma HIV-1 RNA in the 10 TDF-treated patients and in 25 protease inhibitor-naive subjects treated with ritonavir monotherapy were nearly identical. CONCLUSIONS The reduction in plasma HIV-1 RNA with TDF monotherapy was comparable with the decline observed in previous studies of protease inhibitor monotherapy. TDF is a potent antiretroviral agent and has comparable inherent antiviral activity with that of ritonavir, a potent protease inhibitor. These data support further study of TDF-based regimens in simplified combinations of antiviral agents as initial treatment for chronic HIV-1 infection.