Expression of the drug-metabolizing enzyme cytochrome P4502D6 (CYP2D6) is predominantly under genetic control, and enzyme-inducing drugs have little influence on its activity. We studied the activity of CYP2D6 during pregnancy. One hundred forty pregnant women were genotyped for CYP2D6. Seventeen of them (four poor metabolizers, seven heterozygous extensive metabolizers, and six extensive metabolizers) were phenotyped with dextromethorphan in late pregnancy and 7 to 11 weeks after parturition. During pregnancy the dextromethorphan/dextrorphan metabolic ratio was significantly reduced (p = 0.0015) among homozygous and heterozygous extensive metabolizers, indicating increased CYP2D6 activity. In contrast, poor metabolizers showed an increased metabolic ratio during pregnancy. These results are consistent with previous findings of a marked increase in metabolism of the CYP2D6 substrate metoprolol during pregnancy. Both studies indicate an increase in CYP2D6 activity during pregnancy, which may be caused by an induction of the CYP2D6 enzyme.