PURPOSE This study evaluated the effects of CYP2D6 polymorphisms on the pharmacokinetics and dose escalation of controlled-release paroxetine over the dose range of 12.5 - 37.5 mg in healthy Chinese subjects. MATERIALS AND METHODS This was a phase I, open-label, single-dose, three-period crossover study in which 12 healthy subjects received single oral doses of 12.5, 25, and 37.5 mg paroxetine controlled-release tablets with 10-day washout between doses. Serial venous blood samples were collected for 96 hours after study-drug administration and analyzed with LC-MS/MS. CYP2D6 genotypes were tested by PCR and direct DNA sequencing. Pharmacokinetic parameters of paroxetine were calculated using noncompartmental analysis with WinNonlin software. The linearity of paroxetine pharmacokinetics was assessed using a linear mixed-effect model. RESULTS The exposure for paroxetine with regard to mean AUC<sub>0-inf</sub> in the extensive metabolizer (EM)<bold> </bold>group was 10.3-, 3.6-, and 3.2-fold lower at the doses of 12.5, 25, and 37.5 mg paroxetine, respectively, than that in the intermediate metabolizer (IM) group. There was no apparent dose proportionality over the range of 12.5 - 37.5 mg in either the EM or IM groups. From 12.5 to 25 mg paroxetine, the mean ratios of C<sub>max</sub>/dose and AUC<sub>0-inf</sub>/dose were 2.04 and 2.40 in the EM group and 0.93 and 1.00 in the IM group, respectively. From 12.5 to 37.5 mg paroxetine, the mean ratios of C<sub>max</sub>/dose and AUC<sub>0-inf</sub>/dose were 4.04 and 4.08 in the EM group and 1.60 and 1.82 in the IM group, respectively. CONCLUSION The pharmacokinetics and dose escalation of controlled-release paroxetine after a single administration over the dose range of 12.5 - 37.5 mg were affected by CYP2D6 polymorphisms. The increase of drug exposure associated with an increase in the paroxetine dose was more pronounced in the CYP2D6 EMs than in the IMs. .