Collaboration between the University of Pisa, Italy, and the University of Tennessee, Memphis, U.S.A., on patients presenting with major depressive episodes (in the absence of nonaffective psychiatric illness) focused on the detection of depressive and hyperthymic temperaments. From our data on symptomatology, family history and course of 538 such patients, several findings emerge of cardinal relevance to genetic studies. Hyperthymic temperament, observed more commonly in men, appears as one pole of an attenuated form of manic-depressive illness. Thus, major depressives with this temperament have high rates of bipolar family history, even in the absence of hypomanic and manic episodes. The depressive temperament, more prevalent in women, is correlated with earlier onset and higher number of depressive episodes, greater severity of the Hamilton Rating Scale for Depression (HAM-D), as well as higher familial loading for mood disorders, compared with major depressives without this temperament. Building on Akiskal's latest model on the multifactorial origin of mood disorders, we submit that these temperamental dysregulations constitute the intermediate step between predisposing familial-genetic factors in affective illness and gender-related clinical expressions of mood disorders. The authors recommend that future high-risk prospective studies and genetic investigations should include measures of affective temperament.