In our extensive synthesis and screening program for anti-HIV compounds, we have recently found that a novel series 1,2,5-thiadiazole derivatives are highly potent and selective inhibitors of HIV-1 replication. In the screening assays, MT-4 cells were infected with HIV-1 I I I B and incubated in the presence of varying concentrations of the test compounds. After a 4- or 5-day incubation period, the number of viable cells were determined by the MTT method. Approximately 200 compounds were synthesized and examined for their anti-HIV-1 activities in MT-4 cells. Among them, more than 100 compounds proved inhibitory to HIV-1 replication at concentrations that were significantly lower than their cytotoxic thresholds. 4-Phenyl-1,2,5-thiadiazole-3-yl N,N-dimethylcarbamate was the first compound of which anti-HIV-1 activity was identified. Its 50% effective concentration (EC 5 0 ) and the 50% cytotoxic concentration (CC 5 0 ) were 23 and 183μM, respectively. Introduction of chlorine atoms into the 2,6-positions of the phenyl group led to significant increase of activity (EC 5 0 =240nM). Furthermore, with regard to the carbamate group, the compounds having N-methyl-N-propylcarbamate moiety showed the most potent anti-HIV-1 activity. Consequently, the obtained compound 4-(2,6-dichlorophenyl)-1,2,5-thiadiazole-3-yl N-methyl-N-propylcarbamate (RD4-2024) inhibited HIV-1 replication in MT-4 cells at a concentration of 13nM. Its selectivity index (ratio of CC 5 0 to EC 5 0 ) was greater than 10,000. This compound appears to be worth pursuing as a candidate drug for the chemotherapy of HIV-1 infections.