This study employs a prospective design to examine possible personality, drug use, stressful life event, and social support-related variables associated with the onset of a depressive episode in a cohort of psychoactive drug using young adults. Two waves of data, collected one year apart, were available on 942 individuals. Cases (n = 62) were free of depressive symptoms at time 1 but reported significant symptomatology at time 2 as measured by the depression subscale of the Brief Symptom Inventory. Controls (n = 490) were those free of depressive symptoms at both time points. In multivariate analyses, users of the central nervous system depressant methaqualone had a nearly four-fold elevated risk for depressed mood as compared to nonusers. Additional risk factors significant after multivariate adjustment included lower self-esteem at time 1 and negative life events. These results highlight the multifactorial nature of depressive symptomatology.