The potential role of hydroxyurea in the treatment of human immunodeficiency virus (HIV) infection was first supported by in vitro experiments that demonstrated control of viral production in activated and resting T cells. More recently, controlled clinical trials demonstrated that the addition of hydroxyurea to nucleoside-including regimens (chiefly of didanosine but also of stavudine and lamivudine) enhances their antiviral potency. It is believed that the cytostatic effect of hydroxyurea is at least partially responsible for its antiviral effect, through the down-modulation of cellular proliferation. Such an effect has also been credited for the blunted CD4 T cell responses that are characteristically observed when hydroxyurea is added to nucleoside-including regimens. The adjunctive antiviral effect of hydroxyurea-as well as its favorable dosing schedule, safety profile, and cost-makes it a very attractive addition to our therapeutic armamentarium. Further research is urgently needed to delineate the most appropriate use of this compound in the setting of HIV antiretroviral therapy.