As part of a study of the possible subgroups of unipolar affective disease, 27 families were ascertained as depression spectrum disease (DSD) families. The purpose of this study was an investigation of the linkage relationships between DSD and 30 genetic markers using the robust sib-pair and lod-score methods. Using the sib-pair methods, evidence for linkage was found with orosomucoid (ORM) on chromosome 9q (p = 0.006), regardless of whether only individuals with unipolar depression, alcoholism, or antisocial personality were considered to be affected, or whether individuals with any psychiatric disorder were considered to be affected. Weak evidence of linkage with ORM was corroborated using lod-score methods when a narrow definition of depression spectrum disease was used, although stronger evidence of linkage was found with ORM when any psychiatric disorder was considered to be affected. The maximum lod-score for ORM was 1.68 at a male recombination fraction of 0.23 and a female recombination fraction of 0.01.