Multiple sclerosis is a chronic disease, likely to condition patients' daily living and quality of life: given the unpredictability of frequency and severity of the attacks, patients experience a high level of uncertainty. While there have been many analyses whose purpose was to monitor multiple sclerosis (MS) patients' quality of life, the role of uncertainty, that is peculiar to the disease, has not been adequately considered so far. The present study is aimed at filling this gap by validating for Italian MS patients the Mishel's Uncertainty Illness Scale (MUIS). The MUIS has been developed in the USA context in order to assess four aspects of uncertainty: ambiguity, complexity, inconsistency and unpredictability. It has been largely applied in the cancer, cardiac and chronic illness population. Data employed in this study have been collected at two neurological centres in Messina (IRCCS Centro Studi Neurolesi "Bonino Pulejo" and Policlinico di Messina) in the first semester of 2013 and refer to 120 MS patients. The confirmatory factor analysis described in this study validates two of the four dimensions of MUIS, namely ambiguity and inconsistency. The validation, though partial, of the MUIS, allows the use of this instrument in studies investigating quality of life for Italian patients.