The Symbol Digit Modalities Test (SDMT) is a particularly sensitive measure of cognitive dysfunction in patients with multiple sclerosis (MS). While computerized versions have been developed for use in functional magnetic resonance imaging (fMRI), none has been validated in MS patients. The aim of this study was to validate a new computerized version of the SDMT for use in MS patients. We developed a novel computerized version of the SDMT (c-SDMT) which was completed by 119 MS patients and 38 healthy controls. Our version consisted of eight timed trials of nine symbols. Both groups also underwent cognitive testing with the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) which included the 90-s paper SDMT (p-SDMT) scored according to the number of correct responses per each 15-s interval. The sensitivity and specificity of the c-SDMT and p-SDMT to detect overall cognitive impairment on the BRB-N was determined. MS patients performed significantly worse than controls on both the c-SDMT (t = -6.1, p < 0.001) and p-SDMT (t = 5.7, p < 0.001). More MS patients were impaired on the c-SDMT than the p-SDMT (37% vs. 29%). The sensitivity and specificity of the SDMT was as follows: 71% and 84%, respectively, for the c-SDMT, and 67% and 95%, respectively, for the p-SDMT. Both versions detected a significant group × time effect over the course of the individual trials, although the pattern of responses differed between them. Good test-retest reliability for the c-SDMT was shown (ICC = 0.94). The results support the validity of this version of the c-SDMT as a sensitive measure of cognitive dysfunction in MS. The methodology is also fMRI compatible.