Cognitive dysfunction (affecting particularly attention and working memory) occurs early in patients with multiple sclerosis. Previous studies have focused on identifying potentially adaptive functional reorganization through recruitment of new brain regions that could limit expression of these deficits. However, lesion studies remind us that functional specializations in the brain make certain brain regions necessary for a given task. We therefore have asked whether altered functional interactions between regions normally recruited provide an alternative adaptive mechanism with multiple sclerosis pathology. We used a version of the n-back task to probe working memory in patients with early multiple sclerosis. We applied a functional connectivity analysis to test whether relationships between relative activations in different brain regions change in potentially adaptive ways with multiple sclerosis. We studied 21 patients with relapsing-remitting multiple sclerosis and 16 age- and sex-matched healthy controls with 3T functional MRI. The two groups performed equally well on the task. Task-related activations were found in similar regions for patients and controls. However, patients showed relatively reduced activation in the superior frontal and anterior cingulate gyri (P > 0.01). Patients also showed a variable, but generally substantially smaller increase in activation than healthy controls with greater task complexity, depending on the specific brain region assessed (P < 0.001). Functional connectivity analysis defined further differences not apparent from the univariate contrast of the task-associated activation patterns. Control subjects showed significantly greater correlations between right dorsolateral prefrontal and superior frontal/anterior cingulate activations (P < 0.05). Patients showed correlations between activations in the right and left prefrontal cortices, although this relationship was not significant in healthy controls (P < 0.05). We interpret these results as showing that, while cognitive processing in the task appears to be performed using similar brain regions in patients and controls, the patients have reduced functional reserve for cognition relevant to memory. Functional connectivity analysis suggests that altered inter-hemispheric interactions between dorsal and lateral prefrontal regions may provide an adaptive mechanism that could limit clinical expression of the disease distinct from recruitment of novel processing regions. Together, these results suggest that therapeutic enhancement of the coherence of interactions between brain regions normally recruited (functional enhancement), as well as recruitment of alternative areas or use of complementary cognitive strategies (both forms of adaptive functional change), may limit expression of cognitive impairments in multiple sclerosis.