Ca_v2.3 (E/R-type) voltage-gated calcium channels (VGCC) are potential targets for antiepileptics, and are involved in the pathogenesis of absence epilepsy, human juvenile myoclonic epilepsy and epileptiform activity in CA1 neurons. Electroencephalographic analyses, seizure susceptibility testing and a histomorphological characterization of Ca_v2.3^-^/^- mice was performed to unravel the functional relevance of Ca_v2.3 in ictogenesis. Ca_v2.3 deficient mice were analyzed for spontaneous epileptiform discharges using electrocorticographic and deep intracerebral recordings. Convulsive seizure activity was induced by 4-aminopyridine or pentylenetetrazol. Both electrocorticographic and deep intrahippocampal recordings exhibited no spontaneous epileptiform discharges indicative of convulsive or non-convulsive seizure activity during long-term observation. Gross histology and expression levels of other voltage-gated Ca^2^+ channels remained unchanged. Surprisingly, PTZ-induced seizure susceptibility was dramatically reduced in Ca_v2.3-deficient mice whereas 4-AP sensitivity remained unchanged. Ca_v2.3 ablation results in seizure resistance strongly supporting recent findings in CA1 neurons that