Despite a large therapeutic arsenal of old and new antiepileptic drugs (AEDs), there remains a substantial unmet need for the patients with refractory (AED-resistant) epilepsy. Animal models of refractory epilepsy are needed for at least two goals; (1) better understanding of the mechanisms underlying resistance to AEDs, and (2) development of more efficacious AEDs for patients with refractory seizures. It is only incompletely understood why two patients with seemingly identical types of epilepsy and seizures may respond differently to the same AED. Prompted by this well-known clinical phenomenon, we tested whether epileptic rats from the same epilepsy model respond differently to AEDs and previously discovered phenobarbital (PB) responsive and resistant animals in groups of rats in which epilepsy had been induced by sustained electrical stimulation of the basolateral amygdala (BLA). In the present study, we used the same approach for the widely used pilocarpine model of temporal lobe epilepsy. Epileptic rats from this model were continuously video/EEG monitored over seven consecutive weeks, starting with a predrug control period of two weeks, then two weeks of daily treatment with PB at maximum tolerated doses, and finally a postdrug control period of three weeks. In those rats that were included in response selection, 50% did not adequately respond to PB, whereas PB significantly decreased seizure frequency and severity in another 50% of the animals. Responders and nonresponders did not differ in predrug seizure frequency, PB plasma levels or hippocampal neurodegeneration, but behavioral differences were observed in anxiety models. These findings demonstrate that in the pilocarpine model, similar to epilepsy patients, epileptic rats differ in their response to an AED, which is most likely due to as yet unknown genetic factors.