BACKGROUND: A Food and Drug Administration advisory in 2006 warned against the off-label use of quinine sulfate and its derivatives in the treatment of muscle cramps. Physicians are faced with a difficult scenario in choosing a treatment regimen for patients with muscle cramps. This American Academy of Neurology assessment systematically reviews the available evidence on the symptomatic treatment of muscle cramps. METHODS: A total of 563 potential articles were reviewed, of which 24 met the inclusion criteria of prospective trials evaluating the efficacy of a particular treatment on muscle cramps as a primary or secondary outcome. RESULTS: There are Class I studies showing the efficacy of quinine derivatives for treatment of muscle cramps. However, the benefit is modest and there are adverse effects from published prospective trials as well as case reports. There is one Class II study each to support the use of Naftidrofuryl, vitamin B complex, lidocaine, and diltiazem in the treatment of muscle cramps. Recommendations: Although likely effective (Level A), quinine derivatives should be avoided for routine use in the management of muscle cramps because of the potential of toxicity, but in select patients they can be considered for an individual therapeutic trial once potential side effects are taken into account. Vitamin B complex, Naftidrofuryl, and calcium channel blockers such as diltiazem are possibly effective and may be considered in the management of muscle cramps (Level C). Further studies are needed to identify agents that are effective and safe for the treatment of muscle cramps.