We performed a functional MRI (fMRI) study during the execution of the Paced Visual Serial Addition Task (PVSAT) in 9 patients with a clinically isolated syndrome suggestive of multiple sclerosis (CIS), 9 patients with clinically definite multiple sclerosis (CDMS), and 18 matched healthy control subjects. In controls, the PVSAT elicited a fronto-parietal network with cerebellar activation which we expected for this kind of working memory test and which indicates that this PVSAT version is an appropriate tool for measuring functional changes during a cognitive task. Although there were no significant differences in the actual test results of patients vs. controls, CDMS and CIS patients activated distinct cerebral networks in their attempt to solve the fMRI-PVSAT. Compared to CIS patients, CDMS patients showed increased hippocampal and parahippocampal activation, suggesting the need to additionally support their working memory. In contrast, compared to CDMS patients and healthy controls, CIS patients demonstrated stronger activation of the anterior cingulate cortex, which might indicate focused involvement of executive processes. On the PASAT (Paced Auditory Serial Addition Task) patients also performed similarly to controls but they showed decreased scores on most of the sub-tests of the Wechsler Memory Scale. Based on our observations using the fMRI-PVSAT, we hypothesize that distinct differences in cognitive processing occur with the evolution of MS and that, at these early stages of the disease, they cannot be detected with sufficient sensitivity using only the PASAT.