To study the effects of whole‐body cryostimulation (WBC) on fatigue and functional status in multiple sclerosis (MS) patients with different levels of fatigue.Two groups of 24 MS patients with fatigue were studied. At the beginning of the study, the first group presented a Fatigue Severity Scale (FSS) score between 38 and 42 (low‐fatigue (LF) group), and the second group had an FSS score between 48 and 52 (high‐fatigue (HF) group). Both groups were matched for age and sex. All patients were exposed to 10.3‐min session of WBC (one exposure per day at −110°C or lower). Functional status was assessed before and after the series of WBC exposures using the Rivermead Motor Assessment (RMA), the Multiple Sclerosis Impact Scale (MSIS‐29), and the Expanded Disability Status Scale (EDSS). The RMA was estimated in three sections: gross function (RMA1), leg and trunk (RMA2), and arm (RMA3). MSIS‐29 consists of two subscales assessing the physical (MSIS‐29‐PHYS) and psychological (MSIS‐29‐PSYCH) status.In both groups, the WBC sessions induced a significant improvement in the functional status and in the feeling of fatigue. However, the changes observed in HF patients were significantly greater than those observed in LF patients, especially in the MSIS‐29‐PHYS, MSIS‐29‐PSYCH, RMA1, and RMA3. The changes observed in the EDSS, RMA2, and FSS were similar in both groups.WBC appears to be effective in improving functional status and the feeling of fatigue in patients with MS and especially in those who are the most fatigued.