AimsTo determine the effect ofCYP2C8genotype and of fluvoxamine on the pharmacokinetics of rosiglitazone.MethodsTwenty‐three healthy subjects with the following genotypes were included in a two‐phase, open‐label, cross‐over trial:CYP2C8*3/ *3(n = 3),CYP2C8*1/ *3(n = 10) andCYP2C8*1/ *1(n = 10). In Phase A, the subjects were given 4 mg rosiglitazone as a single oral dose. In Phase B, the subjects were treated with multiple oral doses of 50 mg fluvoxamine maleate for 3 days prior to the single oral administration of 4 mg rosiglitazone. Plasma concentrations of rosiglitazone and relative amounts ofN‐desmethylrosiglitazone were measured in both phases for 24 h after drug administration.ResultsThe pharmacokinetics of rosiglitazone andN‐desmethylrosiglitazone were not significantly different between theCYP2C8genotypic groups. Fluvoxamine caused a statistically significant (P = 0.0066) increase in the AUC0–∞of rosiglitazone, with a geometric mean ratio of 1.21 [95% confidence interval (CI) 1.06–1.39]. The elimination half‐life (t1/2) was also significantly higher (P = 0.0203) with a geometric mean ratio of 1.38 [95% CI 1.06–1.79]. The coadministration of fluvoxamine had no influence on the pharmacokinetics ofN‐desmethylrosiglitazone.ConclusionThe importance of theCYP2C8*3mutation in thein vivometabolism of rosiglitazone could not be confirmed. Fluvoxamine increased the AUC0–∞andt1/2of rosiglitazone moderately and hence may be a weak inhibitor of CYP2C8.