Genetic linkage between manic depression and DNA markers on the short arm of chromosome 11 was first reported in 1987 but not supported by further analyses. However, genetic markers at the tyrosine hydroxylase (TH) gene located within this region have been reported to show allelic association with the affective disorder phenotype. We present the results of a linkage analysis using polymorphic DNA segments within the TH gene and the nearby dopamine D4 receptor (DRD4) gene in 6 families multiply affected with affective disorder. Small positive Lod scores were obtained in 2 of 6 pedigrees with the TH polymorphism which may be indicative of genetic heterogeneity.