We found low levels of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) in a subgroup of children with opsoclonus-myoclonus, a pervasive neurological disorder that disables previously normal infants and children. As part of a systematic study to define the neuropharmacologic basis of opsoclonus-myoclonus, five chronically affected children were enrolled in an open, randomized, two-period, dose-ranging, double-blind, cross-over pilot clinical trial designed to compare the antimyoclonic properties of oral 5-hydroxy-L-tryptophan (L-5-HTP) with placebo. Subjects received an increasing L-5-HTP dose from 2 to 15 mg/kg/day as well as oral carbidopa throughout the study but were on no other drugs. Subjective improvement was reported in two subjects, but none showed significantly improved scores on rating scales for myoclonus, opsoclonus, and ataxia, even after further treatment with L-5-HTP for 1–3 months. After treatment, three patients had worse emotional and behavioral problems, and the electroencephalograms of two showed mild slowing but normalized during washout. Blood tests to evaluate hematologic, renal, and hepatic systems showed no changes and no evidence of the eosinophiliamyalgia syndrome. None of the subjects exhibited seizures or worsening of myoclonus. Two patients had very low predrug CSF 5-HIAA levels, but CSF 5-HIAA did not appear to correlate with response to L-5-HTP. The data suggest that L-5-HTP with carbidopa can be used safely in children using our dosing schedule. However, behavioral side effects, which tended to be exacerbations of severe baseline difficulties, though reversible, were prohibitive. Serotonin may play a role in the chronic neurobehavioral problems of opsoclonus-myoclonus. The data support our hypothesis of biochemical subgroups of opsoclonus-myoclonus based on CSF neurochemical studies.