Four hundred and forty-two patients who had plasma viral loads of more than 2,500 copies/ml on standard antiretroviral therapy and CD4 counts greater than 200 cells/mm3 were randomized to placebo or 120 mg/d of adefovir dipivoxil. The median plasma viral load for the cohort was 9,800 copies/ml, and CD4 count was 355 cells/mm3. The adefovir group had a 0.4 log drop in plasma viral load, compared to no decrease in the placebo group. CD4 lymphocyte counts increased by 5 cells by week 24 among those patients who received adefovir. There were similar levels of study drug discontinuation in the adefovir (21%) and the placebo (17%) groups. By 24 weeks, 29% of the adefovir group and 26% of the placebo group added an additional antiretroviral. Grade 3 or 4 adverse events were reported by 8.2% of those receiving adefovir, and 5.4% of those in the placebo group (p=0.26). Grade 2 or greater adverse events were more common in the adefovir group compared to those who received placebo. Only 1% of the patients who received adefovir experienced renal tubular abnormalities by week 24, but this went up to 31.9% of the small number of patients who had been followed to week 48. The data suggest that the addition of adefovir to the regimens of patients whose viral load has rebounded, or never fully suppressed, can result in further viral load reductions, and general tolerability. In current treatment practice, several drugs would have been changed in a failing regimen, so it is likely that the real world practice could result in even better virologic results. This study also corroborates the need for clinicians who are following patients on longterm adefovir to continue to carefully monitor renal function.