Accumulation of central nervous system (CNS) pathology affects cognitive processing speed and efficiency and is thought to underlie attentional and executive deficits in multiple sclerosis (MS). Most clinical neuropsychological tests are multifactorial and are limited in their sensitivity to specific cognitive processes. This may, in part, account for the low to moderate correlations between clinical test results and magnetic resonance imaging (MRI) indices of brain pathology. We compared the ability of a clinical and an experimental test of cognitive processing speed to differentiate domain-specific cognitive changes in MS, and examined relations between test performance and MRI measures of brain pathology. Twelve MS patients and 12 controls completed the Paced Auditory Serial Addition Test (PASAT) and the Attention Networks Test-Interactions (ANT-I), a computerized response latency task. Subjects also had MRI scans that included T1, T2, and fluid-attenuated inversion recovery (FLAIR) sequences that provided global and localized volumetric measures. Patients made more errors on the PASAT and were slower on the ANT-I. The ANT-I also revealed specific deficits in response inhibition. In addition, ANT-I performance was associated with changes in a number of MRI measures, which was not the case for the PASAT. Reaction time paradigms that manipulate within-task demands on distinct cognitive functions may provide meaningful markers of brain disease burden in MS.