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Background: Ceramide is involved in regulating metabolism and energy expenditure, and its abnormal myocardial accumulation may contribute to heart injury or lipotoxic cardiomyopathy. Whether ceramide can modulate the electrophysiology of pulmonary veins (PVs) remains unknown., Materials and Methods: We used conventional microelectrodes to measure the electrical activity of isolated rabbit PV tissue preparations before and after treatment with various concentrations of ceramide with or without H 2 O 2 (2 mM), MitoQ, wortmannin or 740 YP. A whole-cell patch clamp and fluorescence imaging were used to record the ionic currents, calcium (Ca 2+ ) transients, and intracellular reactive oxygen species (ROS) and sodium (Na + ) in isolated single PV cardiomyocytes before and after ceramide (1 μM) treatment., Results: Ceramide (0.1, 0.3, 1 and 3 μM) reduced the beating rate of PV tissues. Furthermore, ceramide (1 μM) suppressed the 2 mM H 2 O 2 -induced faster PV beating rate, triggered activities and burst firings, which were further reduced by MitoQ. In the presence of wortmannin, ceramide did not change the PV beating rate. The H 2 O 2 -induced faster PV beating rate could be counteracted by MitoQ or wortmannin with no additive effect from the ceramide. Ceramide inhibited pPI3K. Ceramide reduced Ca 2+ transients, sarcoplasmic reticulum Ca 2+ contents, L-type Ca 2+ currents, Na + currents, late Na + currents, Na + -hydrogen exchange currents, and intracellular ROS and Na + in PV cardiomyocytes, but did not change Na + -Ca 2+ exchange currents., Conclusion: C2 ceramide may exert the distinctive electrophysiological effect of modulating PV activities, which may be affected by PI3K pathway-mediated oxidative stress, and might play a role in the pathogenesis of PV arrhythmogenesis., (© 2021 Stichting European Society for Clinical Investigation Journal Foundation. Published by John Wiley & Sons Ltd.)