Spatial discrimination of ibotenic acid-lesioned C57BL/6 (B6) and DBA/2 (D2) mice was tested in two-choice water maze and plus maze tasks. B6 but not D2 mice learned the spatial discrimination in the water maze, but strains did not differ in learning a spatial discrimination in the plus maze paradigm. Ibotenic acid lesions of the hippocampus impaired percentage correct choices in the water maze spatial discrimination task in B6 but not in D2 mice, the latter of which may have been due to a floor effect. Furthermore, lesioned mice were more thigmotaxic, the distance travelled until a choice was made was longer and animals made more errors of omission. Despite the poor performance during water maze acquisition, lesioned animals, as well as sham-lesioned D2 mice, eventually acquired some place response in the water maze, as was evident when the location of the platform was reversed. However, hippocampus-lesioned mice of both strains were impaired when tested in the plus maze spatial discrimination task. Thus, ibotenic acid-induced lesions of the hippocampus impair acquisition of spatial discrimination in mice. These deficits were strain-dependent and likely comprise impaired accuracy as well as changes in non-mnemonic types of behaviour. Importantly, lesions in both strains impaired spatial learning, and whether a deficit was seen in mice of the D2 strain seemed to depend on the demands of the task.