The objective was to evaluate the effects of therapeutic dietary supplements and drugs on cognitive function in subjects with Down syndrome. The study design was a systematic review of randomized controlled trials of dietary supplements and/or drugs reporting any assessment of cognitive function in subjects with Down syndrome. Eleven trials were identified with 373 randomized participants. None of the trials reported cognitive enhancing effect in subjects with Down syndrome. Meta-analysis was not conducted due to the heterogeneous nature of the population, interventions and outcome measures used. Overall, the quality of the trials was poor with few subjects and generally inadequate allocation concealment of the treatments given. This comprehensive systematic review provides no positive evidence that any combination of drugs, vitamins and minerals enhance either cognitive function or psychomotor development in people with Down syndrome. However, because of the small number of subjects involved and the overall unsatisfactory quality of the trials, an effect cannot be excluded at this point. At present there is no justification for the use of such regimes outside the context of large well designed trials. Parents of children with Down syndrome should be actively discouraged from giving these 'miracle drugs' to their children.