Abstract Context Research on the effect of osteopathic manipulative therapy (OMTh; manipulative care provided by foreign-trained osteopaths) on chronic symptoms of multiple sclerosis (MS) is lacking. Objective To evaluate the effect of OMTh on chronic symptoms of MS. Methods Patients with MS who were evaluated at the neurology clinic at Genoa University in Italy were recruited for this study. Participants received 5 forty-minute MS health education sessions (control group) or 5 OMTh sessions (OMTh group). All participants completed a questionnaire that assessed their level of clinical disability, fatigue, depression, anxiety, and quality of life before the first session, 1 week after the final session, and 6 months after the final session. The Extended Disability Status Scale, a modified Fatigue Impact Scale, the Beck Depression Inventory-II, the Beck Anxiety Inventory, and the 12-item Short Form Health Survey were used to assess clinical disability, fatigue, depression, anxiety, and quality of life, respectively. Results Twenty-two participants were included in the study (10 in the control group and 12 in the OMTh group). In the OMTh group, statistically significant improvements in fatigue and depression were found 1 week after the final session (P=.002 and P<.001, respectively). An increase in quality of life was also found in the OMTh group 1 week after the final session (P=.36). Conclusion Results demonstrate that OMTh should be considered in the treatment of patients with chronic symptoms of MS.