6-Chloro-2 ,3 -dideoxyguanosine (6-Cl-ddG), which is a lipophilic prodrug of ddG, can exert potent antiretroviral activity against HIV-1 in vitro. The effect of 6-Cl-ddG on acute infection of rhesus monkeys with simian immunodeficiency virus (SIVmac239) were investigated. A dose of 25 mg of 6-Cl-ddG per kg was administered subcutaneously every 8 hr for 10 days. The administration was started 24 hr before challenging with 1 10 2 TCID 5 0 of SIV. The antigenemia (p27 antigen) and the antibody were monitored for up to 29 days after virus inoculation. The peaks of p27 antigenemia significantly delayed in the 6-Cl-ddG treated group than in untreated group. Additionally significant difference was observed in the time for appearance of SIV antibody.We examined the effect of 6-Cl-ddG on an AIDS/ARC rhesus monkey. The clinical features of the monkey infected with SIVmac251/32H were recurrent weight loss, severe diarrhea, neuropathy and the decline of the number of CD4 - and CD8 - cells. 6-Cl-ddG (50mg/kg) was administered subcutaneously every 8 hr for 14 days. The monkey began to show improvement of clinical signs, including weight gain, recovery from diarrhea and disappearance of neuropathy after the onset of drug administration. The ratio of CD4 - /CD8 - and T cell count also increased and the levels were maintained during treatment. On the other hand, B cell count decreased during the treatment. We will also report the efficacy of 6-Cl-ddG (25mg/kg) on three macaques with chronic SIV infection.