Objectives In this study we perform a review of the literature on systemic muscle weakness after administration of botulinum toxin A, to describe the factors that predispose patients to this adverse event and to suggest strategies for prevention. Methods Our search criteria included the terms "Botulinum toxin, Abobotulinum toxin, Dysport ® , Onabotulinum toxin, Botox ® , Incobotulinum toxin and Xeomin ® , muscle weakness, generalized muscle weakness and respiratory distress." Statistical analysis was completed using IBM ® SPSS software. Results We identified 2029 articles and narrowed this to 38 articles referencing 63 specific cases (including two studies form our institution) and 11 case series. Our analysis of 11 case series suggested that systemic muscle weakness is a rare event with botulinum toxin A. Of the 63 cases identified, the most common indications for use were spasticity (49.2%) and neurogenic detrusor overactivity (22.2%). The median age was low at 34 years, and the majority were female (76.2%). Furthermore, 47.6% of the cases were associated with the abobotulinum toxin A formulation. On average, the doses administered were 3.2 times the recommended dose (standard deviation 1.9) suggested for the particular botulinum toxin A formulation and indication. If systemic muscle weakness did occur, indication for botulinum toxin A being upper tract gastrointestinal disorder was associated with more severe impairment (W 2 = 10.2, p = 0.001). Conclusion Based on data from the identified cases of systemic muscle weakness with botulinum toxin A, this adverse event was more common in female, younger, patients with spasticity or neurogenic detrusor overactivity indication or those receiving abobotulinum toxin A formulation and/or higher botulinum toxin A doses. A prevention strategy may include reducing the dose of botulinum toxin A to those recommended by the US FDA.