The D3 dopamine receptor gene is an important candidate gene for schizophrenia, since--because of its almost exclusive expression in the limbic system--it combines the dopamine receptor hypothesis with the limbic system hypothesis of schizophrenia. Pairwise linkage analyses were carried out between the D3 dopamine receptor gene locus (DRD3) and schizophrenia (including major depression among its pleiotropic manifestations). On the basis of these analyses, which assumed a penetrance of 0.71 and a dominant mode of inheritance, we were able to exclude the DRD3 locus with a lod score of -2.50 in four Icelandic pedigrees. The area of exclusion (lod score < -2.00) extended 1.2 centimorgans. We conclude that the genetic predisposition to schizophrenia in these pedigrees is not due to a mutation in the DRD3 locus. However, these results cannot exclude the possibility that a defect in other genes regulating the expression of the D3 dopamine receptor gene could be involved in the pathogenesis of schizophrenia or that linkage analyses in other families or population-based association studies might show a positive result.