<p>Circulating histones released from damaged cells cause secondary impairment to organs, including the heart. Here, we investigate their effects and the underlying pathological mechanisms on isolated ventricular cardiomyocytes. Exogenous H3 or H4 (0.01–1 µg ml⁻¹) induced progressive membrane depolarization, action potential prolongation, membrane potential oscillations resembling early afterdepolarizations, and Ca²⁺ dysregulation. These changes resulted from a histone-induced nonspecific depolarizing current with a linear current voltage relationship, consistent with the formation of transient pores in the sarcolemma. These effects were replicated by the addition of endogenous H3 isolated from media surrounding myocytes where necrosis has been induced. Acetylation by histone deacetylase inhibitors improved cell viability, reduced and delayed the electrophysiological changes observed with nonacetylated H3. Recombinant pan-acetyl H3 eliminated lethal depolarization. Complexes of histone and histone antibodies produced smaller depolarizations after longer exposures and delayed electrophysiological response. This is consistent with neutralization of the positive charges associated with the histone and suggest a novel therapeutic strategy to limit pathology resulting from histone toxicity.</p>