Introduction: Cognitive impairment is frequent in persons with multiple sclerosis (PwMS) and can impact on activities of daily living. The capacity to differentiate real changes from background statistical noise induced by human, instrumentational, and environmental variations inherent to the evaluation would improve cognitive assessments. Objective: To assess the short-term reproducibility of cognitive tests in non-multiple sclerosis (non-MS) persons and PwMS. Methods: Sixty-two PwMS and 19 non-MS persons performed 2 measurements, 1 week apart, of the Symbol Digit Modalities Test (SDMT) and phonological and semantic verbal fluency. Test-retest reliability was evaluated by the intraclass correlation coefficients (ICC) and agreement by standard error of measurement (SEM) and minimum detectable change (MDC). Results: The reliability of the cognitive variables studied had moderate to high ICC values (ICC > 0.8) in both populations. The threshold to consider a significant cognitive modification evaluated by SEM and MDC was lower in PwMS compared with non-MS persons. Conclusions: SDMT and verbal fluency have good short-term reproducibility in PwMS. Specific SEM and MDC cutoffs based on the same design of evaluation (especially retest timing) and to the targeted pathological population (MS vs. healthy) should systematically be used to consider cognitive modification as significant in research protocol as well as in clinical practice.