The effects of dibutyryl cyclic adenosine 3'3':-5'-monophosphate (AMP) and sodium butyrate on the synthesis and secretion of human chorionic gonadotropin (HCG) by trophoblastic and nontrophoblastic human cell lines were studied by radioimmunoassay and pulse-chase labeling techniques. Dibutyryl cyclic AMP stimulated synthesis and secretion of HCG-alpha and HCG-beta subunits by the trophoblastic cell lines JAR and BeWo, whereas butyrate had no effect or decreased secretion. On the other hand, a number of nontrophoblastic cell lines (including the breast carcinoma lines ZR-75-31, BT-20, and MCF-7; the bronchogenic carcinoma line ChaGo; and the cervical carcinoma line HeLa S3) were induced to synthesize and secrete increased amounts of HCG subunits by butyrate, but dibutyryl cyclic AMP had less or no stimulatory effect. The nontrophoblastic brain tumor line CBT was an exception to this general rule in that HCG-beta production was stimulated by dibutyryl cyclic AMP but not by butyrate. In all cases, the drug-induced increase in HCG subunit secretion was directly proportional to the elevation of HCG subunit synthesis. These data suggest that the differential effects of dibutyryl cyclic AMP and butyrate on trophoblastic and nontrophoblastic cells reflect differences in the transcription or translation of HCG subunit genes induced by these agents in the two cell types.