We investigated the frequency of a rare variant of a common microsatellite tetrarepeat allele in the tyrosine hydroxylase gene in 2 independent ethnic groups of schizophrenic patients and their matched controls. In a French population we found the rare variant allele in 5 of 94 (5%) unrelated chronic schizophrenic patients and in none of 145 unaffected controls, thus yielding a significant association (p < 0.01) between schizophrenia and the tyrosine hydroxylase gene. Similarly, in a replication study, we found the rare allele in 4 of 44 (9%) unrelated chronic schizophrenic patients and in none of 44 unaffected controls in a Tunisian population. Albeit the reason of this association is at the moment unknown, it is possible that this polymorphism in the tyrosine hydroxylase gene may be involved in the regulation of its activity.