Cognitive dysfunction is a common finding in schizophrenia. Nevertheless the specific pattern of neuropsychological impairment in schizophrenia compared to other severe mental illnesses has not been intensively studied. Twenty-four patients with schizophrenia belonging to different stages of the disease (11 first-episode patients, 13 patients with multiple episodes), 18 patients with bipolar disorder and 23 healthy control subjects underwent standardized neuropsychological assessment. Statistical analysis of covariance (ANCOVA) demonstrated that, compared to control subjects, patients with schizophrenia performed significantly worse in the trail-making test (P = 0.012), verbal fluency (category letter, P = 0.004), verbal learning/memory (P = 0.005), and the Wisconsin Card Sorting Test (WCST) (P = 0.004 for administered trials; P = 0.025 for perseverative responses, T value) indicating significant deficits in attention and psychomotor performance, and in particular in verbal working memory and cognitive flexibility for schizophrenic patients. A significant difference between schizophrenic and bipolar patients was found only in the WCST. Schizophrenic patients made significantly more perseverative responses (P = 0.002, ANCOVA), indicating a more pronounced and specific deficit in cognitive flexibility and frontally based executive function. In conclusion, these results may suggest a cognitive endophenotype in schizophrenia and underline the role of the prefrontal cortex in schizophrenic pathophysiology.