Milrinone is a newly developed analogue of amrinone possessing potent positive inotropic action. Electrophysiologic actions of the drug have not been reported. In this study microelectrode techniques were used to assess the electrophysiologic effects of milrinone in canine false tendons homogeneously superfused with either normal or high-K Tyrode's solution and in Purkinje fibers mounted in a three-compartment chamber in which the central segment was depressed with an "ischemic" solution. Milrinone (0.2 to 20 micrograms/ml) caused no major changes in the action potential characteristics, refractoriness, or conduction velocity in fibers exposed to normal Tyrode's solution, but markedly improved conduction and abbreviated or eliminated postrepolarization refractoriness in the ischemic gap preparations. The drug also exerted important effects on reflected reentry generated in these preparations. Depending on the initial level of block, milrinone (1) suppressed the arrhythmia, (2) shifted its frequency dependence, or (3) created the conditions that allowed reflection to occur. Similar results were obtained in homogeneously depressed fibers. At similar concentrations, milrinone caused a relatively small enhancement of automaticity. Thus, in addition to its inotropic actions, milrinone produces important electrophysiologic effects. By restoring or improving conduction through areas of depressed conductivity, the drug may exert either antiarrhythmic or arrhythmogenic effects.