The ability of exogenous lysophosphatidylcholine (LPC) to produce electrophysiological abnormalities in cardiac tissues and cardiac arrhythmias in isolated hearts has been well documented. In this study, the arrhythmogenic nature of LPC in the rat, rabbit, and guinea pig hearts was studied. The rat heart was found to be the most susceptible to LPC-induced arrhythmias, while the guinea pig heart was the least susceptible. Perfusion with labelled LPC revealed that the severity of arrhythmias correlates well with the amount of labelled LPC found in the microsomal membrane. The biochemical basis for the differences in the accumulation of LPC in the microsomal membrane of different animal species was investigated. Our results strongly indicate that the LPC level in the microsomal membrane may be regulated by the activity of microsomal lysophospholipase.