Recent research provides evidence that delusional misidentification syndromes (DMS) are associated with cognitive deficits. However, the underlying mechanisms of these deficits are not known. Since the P300 component of event-related potentials (ERPs) is related to fundamental aspects of working memory (WM), the present study is focused on P300 elicited during a WM test in DMS patients, as compared to those of healthy controls. Nine patients with DMS and 11 healthy controls, matched for age, sex and educational level were tested with a computerized version of the digit span test of the Wechsler batteries. Auditory ERPs were measured during the anticipatory period of the test. DMS patients showed significant reductions in P300 amplitude at the right frontal region compared to healthy controls. P300 latency in the central midline brain region was significantly prolonged in the DMS group. Each of these measures classified correctly 90% of the two groups. Moreover, the memory performance of the patient group was significantly lower, relatively to healthy controls. These findings provide evidence supporting the suggestion that DMS is associated with psychophysiological alterations occurring at the right frontal region, which mediates automatic processes, as well as with an irregular allocation of attentional resources, involving the interhemispheric circuitry, possibly due to gray matter degeneration. Finally, present work points to a need for further research investigating the characteristics, causes, course and treatment of severe cognitive deficits associated with DMS.