In the present communication, we report the synthesis and anti-HIV-1 activity of 6-phenylthio and 6-iodo derivatives of l-[(2-hydroxyethoxy)methyl]uracil. Among the compounds prepared, 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (5e) was the most selective anti-HIV-1 agent with a selectivity index of 106. It was highly specific for HIV-1, showing no activity against HIV-2, simian immunodeficiency virus (SIV), simian AIDS related virus (SRV), or Moloney murine sarcoma virus (MSV). 5e manifests its anti-HIV-1 activity through a mechanism different from that of known nucleoside analogues and was less toxic to human bone marrow cells in vitro than AZT. These results suggest that 5e may lead to the discovery of a new class of anti-HIV-1 agents with reduced toxicity.