Cardiac effects of thio-xanthine derivatives, S-caffeine and S-theophylline, were studied on isolated guinea-pig atria and on partially purified cardiac cAMP phosphodiesterase enzymes. Theophylline and caffeine were taken as reference compounds. On electrically driven left atria S-caffeine (0.01-1 mmol/l) decreased contractile tension in a concentration dependent manner. On spontaneously beating atria, the same concentrations of S-caffeine showed negative inotropic as well as negative chronotropic effects. On electrically driven left atria, S-theophylline (0.01-1 mmol/l) increased heart contractile tension but, at higher concentrations, a reversal of the stimulating effect was observed. Both S-caffeine and S-theophylline inhibited bovine heart cAMP phosphodiesterase activity to a comparable extent. Their inhibitory potencies were about three and nine times higher than those of theophylline or caffeine but consistently lower than that of IBMX. The results show that the replacement of O with S in the methylxanthine molecule drastically modifies the effects induced by the drugs on cardiac function without changing those on cAMP phosphodiesterase.