ACTG 175 was randomized, double-blind, placebo-controlled trial to compare monotherapy with zidovudine or didanosine with combination therapy with zidovudine and didanosine or zidovudine and zalcitabine in HIV-1-infected subjects with CD4 cell counts between 200 and 500 per cubic millimeter. Patients were recruited from 43 AIDS Clinical Trials Units and 9 National Hemophilia Foundation sites in the United States and Puerto Rico, and randomly assigned to one of the four treatment groups. Subjects were examined at weeks 2, 4, and 8, and then every 12 weeks thereafter. The primary endpoint was a greater than or equal to 50 percent decline in the CD4 cell count, development of AIDS, or death. Progression to the primary endpoint was more frequent with zidovudine alone (32 percent) than with zidovudine plus didanosine (18 percent), zidovudine plus zalcitabine, or didanosine alone (22 percent). The relative hazard ratios for progression to an AIDS-defining event or death were 0.64 for zidovudine plus didanosine, as compared with zidovudine alone, 0.77 for zidovudine plus zalcitabine, and 0.69 for didanosine alone. This study shows that treatment with zidovudine plus didanosine, zidovudine plus zalcitabine, or didanosine alone slows the progression of HIV disease and is superior to treatment with zidovudine alone. Thus antiretroviral therapy can improve survival in patients with 200 to 500 CD4 cells per cubic millimeter.