Fatigue is considered to be one of the most common and disabling symptoms among individuals with multiple sclerosis (MS). The aim of this study is to investigate if an intensive, short-term inpatient rehabilitation program is able to improve fatigue in MS, and if fatigue is able to negatively influence the clinical and functional outcome of rehabilitation in MS. One-hundred eighty six consecutively recruited MS patients underwent an intensive, short-term inpatient rehabilitation program. Sixty-four of them were selected for this study according to our inclusion criteria and compared to a control group of 22 MS patients who did not follow a rehabilitation program. We measured fatigue symptoms with the Fatigue Severity Scale (FSS) before and after rehabilitation, and classified patients into fatigued (FMS) in the case of an FSS score ≥36 and into non-fatigued MS (NFMS) in the case of an FSS <36. Expanded Disability Status Scale (EDSS) and Functional Independence Measure (FIM) were used as clinical outcome measures of the efficacy of the rehabilitation program. In our sample, an intensive, short-term rehabilitation treatment is able to determine a significant reduction of fatigue symptoms compared to untreated MS patients (p < 0.0001); however, the presence of fatigue at the beginning of the rehab program seems not to have any impact on the clinical and functional outcome of rehabilitation. An intensive inpatient rehabilitation trial decreases symptom of fatigue in MS patients; furthermore fatigue seems not to modify the amelioration of disability and impairment determined by a rehabilitation program.