WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Several antidepressants are metabolized by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6).• The variant allele CYP2D6*4 is the main polymorphism resulting in decreased enzyme activity in Caucasians.• Decreased CYP2D6 enzyme activity potentially leads to higher plasma concentrations of antidepressants.• Consequently, patients carrying the *4 allele are more likely to suffer from adverse drug reactions such as hyponatraemia. WHAT THIS STUDY ADDS • The association between CYP2D6 genotype and serum sodium concentration in users of antidepressants has not been examined thoroughly, and most studies suffer from small numbers of poor metabolizers (PMs) of CYP2D6.• This study shows that serum sodium concentrations in users of tricyclic antidepressive drugs are lower in CYP2D6 PMs than in extensive metabolizers.AIMTo study the effect of the CYP2D6*4 polymorphism on serum sodium concentration in users of antidepressants [selective serotonin reuptake inhibitors and tricyclic antidepressants (TCAs)].METHODSIn this population‐based cohort study, all subjects in the Rotterdam Study were included who used an antidepressant at baseline and from whom a blood sample was available in which CYP2D6 genotype and serum sodium concentration could be determined (n= 76). Multivariate linear regression was used to study the association between CYP2D6*4 and serum sodium concentration.RESULTSCYP2D6 poor metabolizers (PMs) (*4/*4) had a significantly lower mean serum sodium concentration in comparison with CYP2D6 extensive metabolizers (EMs) (*1/*1) [difference −3.9 mmol l−1; 95% confidence interval (CI) −0.86, −7.03; P= 0.013]. In CYP2D6*4 heterozygotes (*1/*4) serum sodium concentration was 1.7 mmol l−1 (95% CI −3.48, 0.18) lower compared with CYP2D6 EMs, but this difference was not statistically significant (P= 0.077).CONCLUSIONSThe serum sodium concentration in PMs was lower in users of an antidepressant, especially in TCA users. Therefore CYP2D6 PMs might be at increased risk of developing symptoms of hyponatraemia.