Neurocognitive involvement in multiple sclerosis (MS) is heterogeneous with some authors suggesting a frontal pattern in patients with predominantly frontal lesions. To assess the relationship between the distribution of lesions and two cognitive components (visual N2, auditory P3a) of the event-related brain potential (ERP) receiving contributions from frontal lobe structures, we performed a combined ERP and magnetic resonance imaging (MRI) study. Thirty-four MS patients were assigned to "low lesion volume, (LLV)"(n = 12),"high lesion volume,(HLV)"(n = 12) and"frontal lesion volume, (FLV)" (n = 10) groups according to lesion volume and distribution on T2-weighted MRI-scans of the brain. ERPs in visual and auditory classification tasks as well as neuropsychological tests were carried out in patients and control subjects (n = 15). The index for automatic feature registration, the N2 component with its mainly frontal contribution in the visual task, was significantly reduced in amplitude in the FLV and HLV groups (both p < 0.01 vs. controls). Moreover its amplitude correlated with lesion volume (r=0.64, p < 0.001). In contrast neither P3a nor P3b subcomponents with a multiple generator nature in the auditory task varied systematically with lesion volume or distribution. Total lesion volume rather than predominant lesion arrangement appears to be the most important factor in neurocognitive changes in MS. This is most consistent with the view that MS lesions lead to partial disconnections within widespread cortical networks which in turn produce a pattern of neuropsychological deficits that reflect total lesion load more than lesion distribution.