Using prospective data on 3,170 respondents aged 18 years and over who were at risk for a first-onset major depression from the New Haven site of the Epidemiologic Catchment Area (ECA) study, these analyses assessed the effects of social status, physical health status, and social isolation on first-onset depression in a 1-year period, controlling for demographic characteristics and baseline psychiatric factors. Among the assessed potential risk factors, poverty status [odds ratio (OR = 2.034, P < 0.05)] and confinement to a bed or chair (OR = 4.015, P < 0.05) were independently associated with an increased risk for a first-onset depressive episode when controlling for gender, age, past history of substance abuse, and subclinical depressive symptoms. The effects of poverty, and to a lesser degree homebound status, were substantially reduced when controlling for degree of isolation from friends and family, suggesting that social isolation mediates some of the relationships between social and physical statuses and major depression.