To clarify the suppressant action of diphenylhydantoin (DPH) on digitalis induced arrhythmias the effects of DPH and digoxin were studied alone and in combination, on contractile force, sodium potassium adenosinetriphosphatase (Na+ K+ ATPase) activity, and potassium (K+) balance in dog hearts perfused with Krebs Ringer's solution. Neither control perfusion nor DPH alone (3 x 10-5M) altered Na+ K+ ATPase activity or produced K+ loss; DPH alone depressed contractile force. Digoxin alone (10-6M) caused a 59% rise in contractile force at the onset of arrhythmia along with a net rate of K+ loss (K+ efflux) of 50 ± 12 μmoles/min and a decrease in Na+ K+ ATPase activity from 13.8 to 5.2 μmoles phosphorus/mg protein hour-1 (P<0.001). Perfusion with combined DPH and digoxin delayed toxicity by 13 minutes (or 82%), at which time contractile force was higher (92% above base line, P<0.05), K+ efflux was greater (87 ± 20 μmoles/min), and Na+ K+ ATPase activity was lower (2.6 μmoles/mg hour-1, P<0.05) than they were with digoxin alone. Combined DPH and digoxin perfusion lasting only until the time toxicity appeared with digoxin alone, however, yielded higher Na+ K+ ATPase activity (7.7 μmoles/mg hour-1, P<0.02) and less rise in contractile force (25% above base line, P<0.05). Thus, DPH appeared to retard digoxin induced inhibition of Na+ K+ ATPase activity. Nevertheless, digoxin in the presence of DPH ultimately produced greater inhibition of Na+ K+ ATPase activity, greater increase in contractile force, and greater K+ efflux prior to toxicity than did digoxin without DPH. These findings suggest that the antiarrhythmic effects of DPH cannot be attributed solely to prevention of inhibition of Na+ K+ ATPase activity or to diminution of K+ efflux, two changes characteristically accompanying digoxin administration.