Objective To assess the efficacy and safety of dl-3-butylphthalide in the treatment of the patients with multiple system atrophy (MSA). Methods Totally 40 consecutive MSA patients admitted in our department from March 1st, 2014 to November 23rd, 2015 were prospectively subjected in this study. They were randomly assigned into the experimental group and the control group. The patients from the former group were given dl-3-butylphthalide injection (25 mg, iv, bid) besides routine therapy, and those from the latter group only received the routine therapy. Unified Multiple System Atrophy Rating Scale (UMSARS) was used to evaluate the symptom relief, curative effect and side effect at admission and in 2 weeks and 3 months after the treatment. All the subjects were also assessed with Barthel Index (BI) scale at the beginning and 12 months later for the effect of the treatment on their daily activities. Results (1) There were no significant differences in the age of onset, course and types of the disease, parameters of external anal sphincter electromyogram and cranial magnetic resonance image between the 2 groups (P>0.05), neither in the age, sex, proportions of the patients complicated with hypertension, diabetes and coronary heart disease and in the UMSARS and BI scores (P>0.05). (2) In 2 and 12 weeks after the treatment, the patients of the experimental group had their muscle tone, gait and muscle tremor improved at some extents, and the scores of UMSARS were significantly lower than the control group (P<0.05). But no obvious difference was seen in the BI scores between them even after the 12 weeks’ follow-up (P=0.13). (3) There were no severe side effects in all the subjects in 2 weeks and 3 months after the treatment. Conclusion dl-3-butylphthalide treatment exerts certain effect on the symptoms and UMSARS scores in the MSA patients, with safety and without severe side effect in clinical application.