Objective: Depression (major depression or depressive syndrome) is more prevalent in alcoholic than in nonalcoholic subjects in families with multiple members with alcoholism studied as part of the Collaborative Study on the Genetics of Alcoholism (National Institute on Alcohol Abuse and Alcoholism). First-degree relatives of probands with comorbid alcoholism and depression have a higher prevalence of both disorders than relatives of probands with alcoholism alone, and both groups have a higher prevalence than the relatives of comparison subjects selected without regard to psychopathology. Data from the collaborative study were used to test three phenotypes (comorbid alcoholism and depression, alcoholism or depression, and depression) for genetic lin kage. Method: Genome-wide sibling-pair linkage analyses were performed with the phenotypes comorbid alcoholism and depression, alcoholism or depression, and depression (major depression or depressive syndrome). Analyses were performed in two data sets (initial and replication data sets) from subject groups ascertained with identical criteria, as well as in the combined data set. Results: Peak lod scores on chromosome 1 (near 120 centimorgan) for the alcoholism or depression phenotype were 5.12, 1.52, and 4.66 in the initial, replication, and combined data sets, respectively. The corresponding lod scores on chromosome 2 were 2.79, 0.20, and 3.26; on chromosome 6, they were 3.39, 0.00, and 0.92; and on chromosome 16, they were 3.13, 0.00, and 2.06. Lod scores on chromosome 2 for the comorbid alcoholism and depression phenotype in the three data sets were 0.00, 4.12, and 2.16, respectively. Conclusions: The results suggest that a gene or genes on chromosome 1 may predispose some individuais to alcoholism and others to depression (which may be alcohol induced). Loci on other chromosomes may also be of interest.