BACKGROUND: Event-related potentials (ERPs) are valuable tools for the early detection and monitoring of cognitive impairment in people with Multiple Sclerosis (pwMS) and towards the evaluation of the effectiveness of treatment. The Symbol Digit Modalities Test (SDMT), a screening tool for cognitive dysfunction, is often impaired in pwMS. OBJECTIVE: To explore the ERPs and reaction time (RT) correlates of SDMT as indicators of cognitive impairment in pwMS. METHODS: We developed an EEG-compatible (EEG-SDMT) paradigm. Ninety-two pwMS and twenty-eight healthy controls (HC) underwent ERPs and RT measurement during EEG-SDMT. RESULTS: SDMT-ERPs presented a centro-parietal (Pz electrode) positive peak (P5) with a significantly longer latency in pwMS (611.72 ± 122.30 ms) versus HC (517.29 ± 75.53 ms) (p textless 0.01). RTs and raw scores in the standard SDMT were inversely correlated (r = -.722, p textless .001). CONCLUSION: Our EEG-SDMT paradigm identified neurophysiological correlates of SDMT performance, which was significantly affected in pwMS. Although the P5 showed longer latencies in pwMS, this component did not differentiate between cognitively impaired and preserved individuals, likely because it is still too early to capture higher-order cognitive deficits. In contrast, RTs emerged as a more reliable and sensitive indicator of cognitive performance.