Mutations at the tyrosine hydroxylase or dopamine D2 receptor loci causing manic depressive illness are unlikely in two families reported here. Linkage was excluded for both loci assuming a dominant mode of transmission and for the tyrosine hydroxylase locus also assuming a recessive mode of transmission. The exclusion was significant using models based on severity of psychopathology and a model requiring severe illness also in first-degree relatives. Conservative genetic parameters were used to minimize misclassification.