This study describes detailed patterns of comorbidity between Diagnostic and Statistical Manual of Mental Disorders (4th ed. [DSM-IV]; American Psychiatric Association, 1994) drug use disorders and major depression in the United States for 1992. Data were derived from the National Longitudinal Alcohol Epidemiologic Survey (NLAES), a national probability survey consisting of 42,862 respondents, 18 years old and older, residing in the contiguous United States. The sampling design included oversampling of Blacks and young adults (18-29 years old). Comorbidity rates and associations between DSM-IV drug use disorders (i.e., prescription drugs, sedatives, tranquilizers, amphetamines, cannabis, cocaine, and hallucinogens) and major depression were expressed as odds ratios with confidence intervals adjusted for the complex design characteristics of the NLAES. Comorbidity analyses were presented by gender, ethnicity, and age for past-year, prior-to-past-year, and lifetime diagnoses. The results showed that virtually all odds ratios were significantly greater than 1, demonstrating that comorbidity of a variety of drug use disorders and major depression is pervasive in the general population. Diagnostic and subgroup variations in comorbidity were noted. As expected, the association between drug dependence and major depression was greater than the association between abuse and major depression. The association between abuse and major depression was greater for women than men for prescription drugs, sedatives, tranquilizers, and amphetamines, but not for cocaine or hallucinogens. Men generally demonstrated stronger relations between drug dependence and major depression. Implications of the results are discussed in terms of professional help seeking, the self-medication hypothesis, and differential social-control theory.