BACKGROUND AND PURPOSE: The antioxidant 5-hydroxymethylfurfural (5-HMF) exerts documented beneficial effects in several experimental pathologies and is currently tested as an antisickling drug in clinical trials. In the present study, we examined the cardiovascular effects of 5-HMF and elucidated the mode of action of the drug. EXPERIMENTAL APPROACH: The cardiovascular effects of 5-HMF were studied with pre-contracted porcine coronary arteries and rat isolated normoxic-perfused hearts. Isolated hearts subjected to ischaemia/reperfusion (I/R) injury were used to test for potential cardioprotective effects of the drug. The effects of 5-HMF on action potential and L-type Ca current (I ) were studied by patch-clamping guinea pig isolated ventricular cardiomyocytes. KEY RESULTS: 5-HMF relaxed coronary arteries in a concentration-dependent manner and exerted negative inotropic, lusitropic and chronotropic effects in rat isolated perfused hearts. On the other hand, 5-HMF improved recovery of inotropic and lusitropic parameters in isolated hearts subjected to I/R. Patch clamp experiments revealed that 5-HMF inhibits L-type Ca channels. Reduced I density, shift of I steady-state inactivation curves toward negative membrane potentials and slower recovery of I from inactivation in response to 5-HMF accounted for the observed cardiovascular effects. CONCLUSIONS AND IMPLICATIONS: Our data revealed a cardioprotective effect of 5-HMF in I/R that is mediated by inhibition of L-type Ca channels. Thus, 5-HMF is suggested as a beneficial additive to cardioplegic solutions, but adverse effects and contraindications of Ca channel blockers have to be considered in therapeutic application of the drug.