Background: To describe transitions to comorbidity within a 3-year period in three cohorts of subjects with at baseline a 12-month pure mood, anxiety or substance use disorder but no lifetime history of any other disorder category. To assess the role of personal and social vulnerability factors, life events, clinical factors and functional disability in the pathway to comorbidity. Methods: Data were derived from the Netherlands Mental Health Survey and Incidence Study (NEMESIS), a prospective epidemiologic study of a representative sample of 7076 adults aged 18-65, interviewed in three waves (baseline, 1 and 3 years after baseline) with the Composite International Diagnostic Interview. Results: 15.2% of 99 pure mood, 10.5% of 220 anxiety and 6.8% of 192 substance use disorder cases became comorbid. Comorbid transition from pure mood disorder was multivariately associated with higher age, external mastery and severity of the disorder. Comorbidity developing from pure anxiety disorder was associated with past and recent stressful life circumstances (childhood trauma, negative life events) and physical functional disability. Predictors of comorbid transition from pure substance use disorder were personal and social vulnerability variables only (high neuroticism, low social support). Limitations: Although NEMESIS was performed among a substantial number of cases, the number of cases with a pure disorder at baseline subsequently developing comorbidity was low. This limited analysing determinants of different comorbid conditions. Conclusions: Risk factors for comorbid transitions vary depending on whether subjects have a primary mood, anxiety or substance use disorder. Interventions aimed at primary prevention of comorbidity to reduce psychiatric burden in populations with a history of pure disorders are indicated in response to clearly identified risk factors.