This study examined risk factor profiles of pure and comorbid 12-month mood, anxiety, and substance use disorder in the general population. Data were derived from the Netherlands Mental Health Survey and Incidence Study, a prospective epidemiologic study in which a representative sample of 7,076 adults age 18-64 years were interviewed with the Composite International Diagnostic Interview. Logistic regression was used to compare subjects with a diagnosis of pure and comorbid disorders with non-psychopathological comparison subjects and to compare subjects with comorbid disorders with those with pure disorder on sociodemographic characteristics, chronic somatic conditions, parental psychiatric history, and childhood traumas and adversities. Only 39.5% of the subjects with a 12-month mood disorder, 59.3% of those with an anxiety disorder, and 75.4% of those with a substance use disorder exhibited the disorder in the pure form. Comorbid anxiety and mood disorders, the most prevalent comorbid condition, showed associations with eight of the nine sociodemographic and long-term vulnerability factors investigated; pure mood disorder and pure anxiety disorder were each linked to only about half of the factors. Female gender, younger age, lower educational level, and unemployment were associated with comorbid anxiety and mood disorders but not with pure mood disorders. The risk profiles of pure anxiety disorder and pure substance use disorder similarly diverged from those of the comorbid conditions. High levels of psychiatric comorbidity exist in the general population. The risk factor profiles for comorbid disorders differ considerably from those for pure disorders. Primary prevention of secondary disorders in populations with a history of a primary disorder are important for reducing psychiatric burden.