Background: The aim of this study was to compare clinical expressions (severity and loneliness), lifestyle factors (substance use), and vulnerability indicators (stressful childhood experiences) in patients with any same-sex attraction versus heterosexual patients diagnosed with depression and/or anxiety disorder. Little is known about this, even though it is now well documented that depression and anxiety are more prevalent among persons with same-sex attraction. Method: Data, derived from the Netherlands Study of Depression and Anxiety (NESDA), allowed us to compare patients with a same-sex (n = 122) and an exclusively opposite-sex (n = 1658) attraction. Persons with same-sex attraction included persons who were attracted to both sexes. Data were collected by means of the Composite International Diagnostic Interview and paper-and pencil questionnaires. Results: Seven percent of the patients reported any same-sex orientation. Clinical expression of depression and anxiety did not differ in relation to sexual attraction. Regarding substance use, same-sex attracted women reported more drug use than heterosexual women (drug use: 16.2% vs. 6.6%, P = 0.003). Regarding stressful childhood experiences, men with any same-sex attraction reported more sexual abuse during childhood than men with a heterosexual orientation (20.4% vs. 8.5%, P = 0.005). Conclusions: For women with same-sex attraction substance use (especially illicit drug use) might be a coping mechanism to deal with existing symptoms or with the minority stressors they have to deal with; for same-sex attracted men stressful childhood experiences might reflect an aspect of etiology.