Many patients with epilepsy suffer from psychiatric comorbidities including depression, anxiety, psychotic disorders, cognitive, and personality changes, but the mechanisms underlying the association between epilepsy and psychopathology are only incompletely understood. Animal models of epilepsy, such as the pilocarpine model of acquired temporal lobe epilepsy (TLE), are useful to study the relationship between epilepsy and behavioral dysfunctions. In the present study, we examined behavioral and cognitive alterations, spontaneous seizures, and neuropathology developing after a pilocarpine-induced status epilepticus in the C57BL/6 (B6) inbred strain of mice, which is commonly used as background strain for genetically modified mice. For this study, we used the same pilocarpine ramping-up dosing protocol and behavioral test battery than in a previous study in NMRI mice, thus allowing direct comparison between these two mouse strains. All B6 mice that survived SE developed epilepsy with spontaneous recurrent seizures. Epileptic B6 mice exhibited significant increases of anxiety-related behavior in the open field and light-dark box, increased locomotor activity in the open field, elevated plus maze, hole board, and novel object exploration tests, and decreased immobility in the forced swimming and tail suspension tests. Furthermore, spatial learning and memory were severely impaired in the Morris water maze, although hippocampal damage was much less severe than previously determined in NMRI mice. B6 mice in which pilocarpine did not induce SE but only single seizures did not exhibit any detectable neurodegeneration, but differed behaviorally from sham controls in several tests of the test battery used. Our data indicate that the pilocarpine model of TLE in B6 mice is ideally suited to study the neurobiological mechanisms underlying the association between seizures, brain damage and psychopathology.