The in vitro effect of single or combined doses of zidovudine (AZT) and dideoxycytidine (ddC) on the production and utilization of interleukin-2 (IL-2) by normal human peripheral blood mononuclear cells (PBMC) was evaluated by measuring IL-2 concentrations in supernatants from PHA-stimulated PBMC cultures. Drugs were added at the beginning of the culture period and left throughout. Whereas AZT alone (1 and 10 microM) caused only a slight increase, ddC alone (1 and 10 microM) and combined AZT/ddC (1 + 1 and 10 + 10 microM) caused a considerable increase. IL-2 gene expression in the drug-treated PBMC did not increase. This finding suggested that the increased supernatant IL-2 accumulations might be caused by a drug-induced down-regulation of the IL-2 receptor alpha (IL-2R alpha, CD25). AZT decreased IL-2R alpha expression, but only slightly. In contrast, ddC alone and combined AZT/ddC decreased the CD25 molecules in a marked and dose-dependent manner. They also markedly reduced IL-2R alpha gene expression. These findings show that the dideoxynucleoside drugs tested left PHA-induced IL-2 gene activation unchanged but decreased IL-2R alpha gene activation, thus down-regulating IL-2R alpha cell-surface protein expression.