Major depression is a relatively common psychiatric disorder that can be quite debilitating. Family, twin, and adoption studies indicate that unipolar depression has both genetic and environmental components. Early age at onset and recurrent episodes in the proband each increase the familiarity of the illness. To investigate the potential genetic underpinnings of the disease, we have performed a complex segregation analysis on 832 individuals from 50 multigenerational families ascertained through a proband with early-onset recurrent unipolar major depression. The analysis was conducted by use of regressive models, to test a variety of hypotheses to explain the familial aggregation of recurrent unipolar depression. Analyses were conducted under two alternative definitions of affection status for the relatives of probands: (1) "narrow," in which relatives were assumed to be affected only if they were diagnosed with recurrent unipolar depression; and (2) "broad," in which relatives were assumed to be affected if diagnosed with any major affective illness. Under the narrow-definition assumption, the model that best explains these family data is a transmitted (although non-Mendelian) recessive major effect with significant residual parental effects on affection status. Under the broad-definition assumption, the best-fitting model is a Mendelian codominant major locus with significant residual parental and spousal effects.