The inhibitory effects of 12 synthetic N6-alkyl cAMPs, 8-substituted cAMPs and cAMP alkylphosphoramidate derivatives (50 or 100 mg/kg, bolus, i.p.) on serum GOT and GPT activities and hepatocyte cytoplasmic vacuolation were examined in male Fischer 344 rats, which were exposed to CCl4 (0.5 mg/kg, p.o.) 30 min prior to the administration of cAMP derivatives. In CCl4-treated rats 6 h later, serum GOT and GPT levels were elevated 10- and 12-fold higher than those of vehicle rats, respectively. Treating CCl4-exposed rats with all cAMP derivatives, except those of alkylphosphoramidate, significantly decreased the levels of serum enzymes. Based on the effects of both serum GOT and GPT elevation, N6-butyl- and N6-heptyl-cAMP were the most potent. It was also observed histopathologically, that both compounds inhibited the occurrence of cytoplasmic vacuolation in CCl4-treated liver cells. This is the first report that cAMP derivatives possess a protective effect in the liver injury model induced by CCl4.