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<jats:title>Abstract</jats:title><jats:p>Cytochrome P450 2C19 (CYP2C19) is a polymorphic enzyme active in the metabolism of for example diazepam and the antidepressants sertraline, citalopram, and escitalopram, whereby allelic variants cause increased (<jats:italic>CYP2C19*17</jats:italic>) or abolished (mainly <jats:italic>CYP2C19*2</jats:italic>) enzymatic activity in drug metabolism. In light of the importance of CYP2C19 in the metabolism of psychoactive substances we considered it of interest to investigate the relationship between CYP2C19 polymorphisms and depressive symptoms in 1,472 subjects of European ancestry (45–98 years old) from the Swedish Twin Registry. Depressive symptoms were assessed using the Center of Epidemiologic Studies Depression (CES‐D) scale. We found that poor metabolizers lacking CYP2C19 activity (PMs, <jats:italic>CYP2C19*2/*2</jats:italic>) had significantly lower levels of depressive symptoms than extensive metabolizers (EMs, <jats:italic>CYP2C19*1/*1</jats:italic>) (<jats:italic>P</jats:italic> = 0.0018). The size of this difference was in the same range as that between subjects reported taking antidepressants (n = 104) and those without antidepressant treatment (<jats:italic>P</jats:italic> &lt; 0.0001). Our results suggest for the first time that the <jats:italic>CYP2C19</jats:italic> polymorphism might be of importance for depressive symptoms, as here shown for older European adults. © 2010 Wiley‐Liss, Inc.</jats:p>