The combination of zidovudine (AZT) and 2',3'-dideoxycytidine synergistically inhibits human immunodeficiency virus type 1 (HIV-1) replication in vitro with AZT-sensitive and AZT-resistant clinical isolates and HIV-1IIIB. Synergy was determined by the median-effect principle and isobologram techniques. Cytotoxicity of the agents was not observed. Clinical trials are ongoing to define the combination's role in HIV-1 therapy.