We have previously demonstrated that declines in c-myc expression precede the induction of c-fos and c-fms transcripts during monocytic differentiation of human leukemia (HL-60 and U-937) cell lines. The present study has monitored the effects of 1-beta-D-arabinofuranosylcytosine (ara-C) on proto-oncogene expression in U-937 cells. The results demonstrate that ara-C inhibits both U-937 proliferation and c-myc expression in a concentration- and time-dependent manner. At non-toxic concentrations of ara-C, these decreases in c-myc RNA occur in the absence of changes in the level of actin transcripts. The results also demonstrate that ara-C increases c-fos but not c-fms expression. Similar findings have been obtained with retinoic acid. Furthermore, although both agents induce a more mature U-937 phenotype, ara-C is a relatively weak inducer of these cells. These findings would suggest that the changes in proto-oncogene expression induced by ara-C may be related to induction of differentiation or the inhibitory effects of this agent on proliferation.