BACKGROUND: Lorazepam is used as premedication for its anxiolytic properties. The UGT2B15 genotype is of importance for the metabolism of lorazepam. The clinical effect of genetic polymorphisms in UGT2B15 genotype on the treatment of anxiety levels in same-day surgery patients receiving lorazepam, however, is unknown. METHODS: Three hundred ninety-eight same-day surgery patients of mixed sex (from a previous double-blinded randomized controlled trial who were assigned to either lorazepam [n = 198] or placebo [n = 200]) were assessed for the UGT2B15*2 variant allele. Anxiety was measured preoperatively and postoperatively by the State part of the State-Trait Anxiety Inventory. The difference between these 2 measurements served as outcome of the study. Analysis of variance was used to assess the State part of the State-Trait Anxiety Inventory difference for interactions among the following factors: UGT2B15 genotype status, treatment condition (lorazepam or placebo), patient sex, and preoperative anxiety score. RESULTS: The anxiety difference was complex in that the interaction of lorazepam and UGT2B15 genotype status also was dependent on the joint effect of patient sex and preoperative anxiety score (F = 7.15, P =.008). Further exploration showed clinical relevant results in patients with high preoperative anxiety scores. Striking was that females with high preoperative anxiety scores and genetically reduced lorazepam glucuronidation (UGT2B15*2 homozygotes) showed more postoperative anxiety reduction than males with the. same genotype. CONCLUSIONS: UGT2B15 genotype contributes to postoperative anxiety reduction after lorazepam premedication. Future research that focuses on patients with high preoperative anxiety scores could help to gain a deeper understanding in the clinical relevance of the interaction between lorazepam and UGT2B15 genotype on postoperative anxiety levels.