This is a study of the familial transmission of Primary Major Depressive Disorder in the families of 235 probands with this disorder ascertained as part of the NIMH-CRB Collaborative Depression Program. Eight hundred and twenty-six interviewed first degree relatives and 109 spouses are included. Research Diagnostic Criteria have been used and interviews were done using the SADS-L schedule. Prior analyses of these data have established the presence of strong secular trends in the age-of-onset and prevalence of Major Depressive Disorder in these families. Accordingly, new methods for the analysis of family data which incorporate secular variation were developed. Non-parametric Survival Analysis, using the Cox Proportional Hazards Model, guided the formulation of a quantitative family transmission model. Then a family analysis was conducted with the Multifactorial Model of Disease Transmission and the Tau Path Analytic Model. Using the non-parametric approach, only the sibs birth cohort, sex and affectational status of the mother were significantly related to the time of onset of illness in siblings. Proband sex, age-of-onset, and the presence of illness in the father were not significant. The quantitative analysis confirmed that more recently born cohorts of individuals had an increased expected lifetime prevalence and a decreased age-of-onset of Primary Major Depressive Disorder. Assortative mating was present and environmental factors common to siblings did not make a significant contribution to the phenotypic variance. Sex specific transmissibilities were found and the transmissibility in females (t2 = 0.62) was significantly greater than that of males (t2 = 0.28). There was a trend for the transmissibility of Primary Major Depressive Disorder to be greater in more recently born cohorts.