Botulinum toxin A is US Food and Drug Administration approved for prophylactic treatment for chronic migraines. To assess botulinum toxin A for the prophylactic treatment of headaches in adults. A search of MEDLINE, EMBASE, bibliographies of published systematic reviews, and the Cochrane trial registries between 1966 and March 15, 2012. Inclusion and exclusion criteria of each study were reviewed. Headaches were categorized as episodic (<15 headaches per month) or chronic (≥15 headaches per month) migraine and episodic or chronic daily or tension headaches. Randomized controlled trials comparing botulinum toxin A with placebo or other interventions for headaches among adults. Data were abstracted and quality assessed independently by 2 reviewers. Outcomes were pooled using a random-effects model. Pooled analyses suggested that botulinum toxin A was associated with fewer headaches per month among patients with chronic daily headaches (1115 patients, -2.06 headaches per month; 95% CI, -3.56 to -0.56; 3 studies) and among patients with chronic migraine headaches (n = 1508, -2.30 headaches per month; 95% CI, -3.66 to -0.94; 5 studies). There was no significant association between use of botulinum toxin A and reduction in the number of episodic migraine (n = 1838, 0.05 headaches per month; 95% CI, -0.26 to 0.36; 9 studies) or chronic tension-type headaches (n = 675, -1.43 headaches per month; 95% CI, -3.13 to 0.27; 7 studies). In single trials, botulinum toxin A was not associated with fewer migraine headaches per month vs valproate (standardized mean difference [SMD], -0.20; 95% CI, -0.91 to 0.31), topiramate (SMD, 0.20; 95% CI, -0.36 to 0.76), or amitriptyline (SMD, 0.29; 95% CI, -0.17 to 0.76). Botulinum toxin A was associated with fewer chronic tension-type headaches per month vs methylprednisolone injections (SMD, -2.5; 95% CI, -3.5 to -1.5). Compared with placebo, botulinum toxin A was associated with a greater frequency of blepharoptosis, skin tightness, paresthesias, neck stiffness, muscle weakness, and neck pain. Botulinum toxin A compared with placebo was associated with a small to modest benefit for chronic daily headaches and chronic migraines but was not associated with fewer episodic migraine or chronic tension-type headaches per month.