Cognitive reserve theory helps to explain the neuropsychological expression of neurologic disease (e.g., Alzheimer's disease; Stern, 2006). Multiple sclerosis (MS) is a neurologic disease characterized by information processing inefficiency and verbal learning and memory deficits. The current study is the first to investigate whether higher cognitive reserve moderates the relationship between MS and cognitive functioning. A word-reading proxy of premorbid intelligence was used to estimate cognitive reserve for 58 persons with MS and 43 healthy controls. Dependent measures of simple processing efficiency, complex information processing efficiency, and verbal learning and memory were administered. There were significant Group x Cognitive Reserve interactions for complex information processing efficiency and verbal learning and memory, such that persons with MS demonstrated deficits relative to controls at lower, but not higher, levels of reserve. No such interaction was found for simple processing efficiency. The protective influence of higher cognitive reserve against disease-related cognitive deficits is discussed.