PURPOSE: To determine whether modification of the connections between cerebellar and prefrontal areas might vary among multiple sclerosis (MS) phenotypes and might be associated with cognitive failure. MATERIALS AND METHODS: Approval of the institutional review boards and written informed consent were obtained from each participant. Stroop-related functional magnetic resonance (MR) imaging activations and effective connectivity abnormalities between the right cerebellum and any other brain regions were assessed by using a psychophysiologic interaction (PPI) analysis from 17 patients with relapsing-remitting (RR), 17 with benign, and 23 with secondary progressive (SP) MS and 18 healthy control subjects (P < .05, corrected at cluster level). Correlations with disease duration, T2 lesion volume, brain volume, and response times (RTs) during the incongruent condition were estimated (P < .001, uncorrected). RESULTS: Activation and PPI analyses showed that, compared with the other groups, RR MS group had abnormal recruitment of regions of the left frontoparietal lobes, whereas compared with RR MS group, SP MS group had abnormal recruitment of the cingulum or precuneus. Benign MS group had increased activation of the right prefrontal cortex, and increased interaction between these regions and the right cerebellum. In healthy controls, RTs inversely correlated with activity of right cerebellum and several frontoparietal regions. In MS, RTs inversely correlated with bilateral cerebellar activity and directly correlated with right precuneus activity. In MS, disease duration inversely correlated with right cerebellar activity and directly correlated with left inferior frontal gyrus and right precuneus activity. Higher T2 lesion volume and lower brain volumes were related to activity in these areas. CONCLUSION: Patients with MS who have various clinical phenotypes experience different abnormalities in activation and effective connectivity between the right cerebellum and frontoparietal areas, which contribute to inefficient cortical reorganization, with increasing cognitive load. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120216/-/DC1.