To evaluate the potential effects of medications with central nervous system (CNS) activity on cognitive function and fatigue in multiple sclerosis (MS), we performed a retrospective analysis of medication use among 70 subjects with MS who were participating in a clinical trial for evaluation of the effects of yoga and exercise programs on cognition and fatigue. Among these MS subjects, 74% were taking at least one potentially CNS-active medication. These 70 subjects were divided into two groups: those taking at least one CNS-active medication (n = 52) and those not on any medications with potential CNS activity (n = 18). We compared assessments of cognitive function and fatigue using an analysis of covariance. MS subjects on CNS-active medication had greater impairment on measures of processing speed, sustained attention, and fatigue than those not on these medications. While these findings do not establish a causal relationship between medication use and cognitive impairment and fatigue, the data indicate that researchers need to control for use of CNS-active medications when conducting studies of cognitive impairment and fatigue in MS subjects.