Multiple Sclerosis (MS) is a disease with a wide-ranging impact on functional status. The aim of the study was to examine the added value of simultaneously evaluating fatigue, personal ADL and handwriting performance as indicators for functional decline among patients with MS. Participants were 50 outpatients with MS and 26 matched healthy controls. Data collection instruments included a disability status scale, the Fatigue Severity Scale (FSS), and the Physical Self-Maintenance Scale (PSMS). Handwriting performance was evaluated by objective computerized measures of the handwriting process (ComPET). Significant differences were found between patients with MS and control subjects in their fatigue level, their PSMS score and In-air time per stroke while writing. The FSS together with specific PSMS items and handwriting measures achieved correct classification of 87.7% of the participants. These results are the first step towards demonstrating the added value of evaluating body function outcomes (fatigue) together with activity performance (handwriting and ADL) to document functional decline among patients with MS. These results may contribute to the development of practical intervention strategies targeted at improving performance abilities among patients with MS.