The objective of this study was to characterize electrophysiologically the basis of the cognitive dysfunction in multiple sclerosis. The cognitive dysfunction experienced by patients with multiple sclerosis has recently become more widely appreciated, but the best means of monitoring such function is unknown. Long-latency cerebral event-related potentials were recorded in a group of patients with relapsing/remitting or secondarily progressive multiple sclerosis and in a group of age-matched normal control subjects. Subjects were presented a series of auditory tones, with one (1,000 Hz) occurring during 86% of the trials (frequent tone) and the other (2,000 Hz) occurring during 14% of the trials (rare tone). Subjects were required to listen to the stimuli and count the occurrence of the rare tones. Cerebral responses recorded from the scalp were averaged separately for the rare and frequent tones. The N1, P2, N2, and P3 components of the long-latency response were all prolonged in latency in patients with MS, as were the N1-N2 and N1-P3 interpeak latencies. In addition, the amplitude of the P2 and P3 peaks was diminished in patients compared with control subjects. Significant correlations were found between the changes in both interpeak latency peak amplitude and the scores on the Mini-Mental State Examination. Electrophysiologic changes occur in MS that are the result of central disease (as opposed to involvement of primary afferent pathways) and correlate with cognitive status. The recording of event-related potentials may thus provide a useful tool, not only as an objective measure of cognitive function in patients with MS, but also as an aid in the evaluation of response to treatment.