Several reports have described salutary effects such as decreased physical aggression and improved social responsiveness being associated with the administration of high doses of pyridoxine and magnesium (HDPM) in open-labeled and controlled studies of patients with autism. Despite this fact, this intervention remains controversial. A 10-week double-blind, placebo-controlled trial was undertaken to examine both the efficacy and safety of HDPM in autism. Twelve patients were enrolled, and 10 patients (mean age 6 years 3 months) were able to complete the study. HDPM at an average dose of 638.9 mg of pyridoxine and 216.3 mg of magnesium oxide was ineffective in ameliorating autistic behaviors as assessed by the Children's Psychiatric Rating Scale (CPRS), the Clinical Global Impression Scale, and the NIMH Global Obsessive Compulsive Scale. Furthermore, no clinically significant side effects were noted during HDPM administration. A trend for a transient change on the CPRS was found that was possibly due to a placebo response. This study raises doubts about the clinical effectiveness of HDPM in autistic disorder.