Adefovir dipivoxil is a novel nucleotide analogue with several promising in vitro anti-human immunodeficiency virus (HIV) characteristics. To evaluate the safety and efficacy of adefovir dipivoxil monotherapy, a randomized, double-blind, placebo-controlled study was initiated involving 72 subjects with moderately advanced HIV disease. Subjects were randomly assigned in a 2:1 ratio to receive adefovir dipivoxil or placebo as a once-daily oral dose for 6 weeks, followed by 6 weeks of open-label adefovir dipivoxil. Two dose levels were studied (125 mg and 250 mg). Adefovir dipivoxil was determined to be safe and well-tolerated when administered for 12 weeks. At week 6, changes in absolute CD4 T cell levels and HIV-1 RNA levels were significantly greater with adefovir dipivoxil than with placebo. These effects were sustained through 12 weeks of treatment. As determined by standard RNA sequencing techniques, only 1 of the 24 subjects who received adefovir dipivoxil (125 mg/day) developed any genotypic change from baseline.