L-5HTP was tested versus placebo in a double-blind crossover study of 27 migraine children aged 6–12 years, who recorded their headaches in a headache diary for 1 month. Twenty-one patients subsequently started the trial. The mean daily dose of L-5HTP was 5 mg/kg body weight, and each treatment period with either L-5HTP or placebo lasted 12 weeks. In group A (L-5HTP-placebo; 10 patients) and group B (placebo-L-5HTP; 11 patients) both L-5HTP and placebo led to a significant reduction of the migraine index and frequency of migraine attacks during the 3rd month of each treatment period. However, we found a treatment x period interaction because the efficacy determinants decreased significantly during the first and the second treatment periods in both groups irrespective of the sequence of treatments. No differences were found between L-5HTP (first period of group A) and placebo (first period of group B).