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Adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1) polymorphisms may influence 5-hydroxytryptamine receptor antagonist efficacy by altering their efflux transportation. We evaluated the influence of ABCB1 polymorphisms on the efficacy of ramosetron compared with palonosetron in managing postoperative nausea and vomiting (PONV) in patients who received intravenous patient-controlled analgesia after spinal surgery.Patients were randomly allocated to receive 2 boluses (20 min before the end of surgery and 24 h after surgery) of either ramosetron 0.3 mg (n=150) or palonosetron 0.075 mg (n=146). The incidence and severity of PONV, fentanyl consumption, and pain intensity were serially assessed for postoperative 48 hours. ABCB1 3435C>T and 2677G>T/A polymorphisms were assessed.The incidences of nausea were similar between the 2 groups in patients with the 3435TT (50% vs. 56%, ramosetron and palonosetron group, respectively, P>0.999) or 2677TT (50% vs. 56%, ramosetron and palonosetron group, respectively, P>0.999). Mild PONV were more frequent in the ramosetron group than in the palonosetron group among patients with 3435TT (91% vs. 33%, P=0.034) and 2677TT (92% vs. 20%, P=0.002) genotypes. The intensity of nausea experienced by ramosetron-group TT genotype patients (1 [1 to 2], 3435TT; 1 [1 to 2.5], 2677TT) was lower than that experienced by ramosetron-group non-TT genotype patients (3 [1 to 6], 3435 non-TT, P=0.030; 3 [1 to 6], 2677 non-TT, P=0.038) and palonosetron-group TT genotype patients (6 [2 to 7], 3435TT, P=0.010; 6 [4 to 7], 2677TT, P=0.002).Compared with palonosetron, ramosetron may be superior for reducing PONV severity, especially in patients with ABCB1 3435TT or 2677TT genotype.