A main component of St. John's Wort (Hypericum perforatum, HP) is hyperforin which has antioxidant properties in dorsal root ganglion (DRG) neurons, due to its ability to modulate NADPH oxidase and protein kinase C. Recent reports indicate that oxidative stress through NADPH oxidase activates TRPM2 channels. HP may be a useful treatment for Ca2+ entry and oxidative stress through modulation of TRPM2 channels in the DRG. We aimed to investigate the protective role of HP on Ca2+ entry and oxidative stress through TRPM2 channels in DRG neurons of rats.The native rat DRG neurons were used in whole-cell patch-clamp, Fura-2 and antioxidant experiments. Appropriate, nontoxic concentrations and incubation times for HP were determined in the DRG neurons by assessing cell viability. The H2O2-induced TRPM2 currents were inhibited by 2-aminoethyl diphenylborinate (2-APB) and N-(p-amylcinnamoyl)anthranilic acid (ACA). TRPM2 current densities and cytosolic free Ca2+ concentration in the neurons were also reduced by HP (2 and 24h). In Fura-2 experiments, cytosolic Ca2+ mobilization was reduced by voltage-gated calcium channel blockers (verapamil+diltiazem, V+D) and HP. Glutathione peroxidase activity and GSH values in the DRG were high in HP, 2-APB and V+D groups although lipid peroxidation level was low in the groups.In conclusion, we observed a protective role for HP on Ca2+ entry through a TRPM2 channel in the DRG neurons. Since over-production of oxidative stress and Ca2+ entry are implicated in the pathophysiology of neuropathic pain and neuronal inflammation, our findings may be relevant to the etiology and treatment of neuropathology in DRG neurons. © 2014 IBRO.