Selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased bleeding tendency. To prospectively quantify the dose-response effects of paroxetine and the influence of the serotonin transporter gene (SLC6A4) promoter polymorphism (5-HTTLPR) on platelet function. Nineteen drug-free psychiatric outpatients (44.5 +/- 10.8 years) were tested before and after 6 weeks of paroxetine treatment (20 mg day(-1)). Based on clinical symptoms, paroxetine dosages were increased (40-50 mg day(-1)) for 6 more weeks in 11 patients. Parameters related to platelet function were assessed by bleeding time, platelet function analyzer (PFA), platelet serotonin, platelet factor 4 (PF4), beta-thromboglobulin (beta-TG), and aggregation tests. Paroxetine 20 mg day(-1) increased mean bleeding time by 1.2 min (95% confidence interval (95% CI) -0.2-2.7) and reduced median platelet serotonin level (463 ng 10(-9) platelets; inter quartile range (IQR) 361-666), and platelet ss-TG concentration (3.1 IU 10(-6) platelets; IQR 0.3-6.0). Other platelet parameters did not change significantly. Serial platelet aggregation tests did not become abnormal. Paroxetine dose-escalation did not further influence platelet function. However, 5-HTTLPR polymorphisms modified these effects: in L(A)/L(A)-carriers, bleeding times did not change (-0.2 min; 95% CI -0.6 to 0.9), while bleeding times significantly increased in <2L(A)-allele carriers (2.3 min; 95% CI 0.5 to 4.07; P = 0.032). Platelet serotonin decreases were larger in patients without L(A)-alleles (868 ng 10(-9) platelets; IQR 585 to 1213) than in > or =1 L(A)-allele carriers (457 ng 10(-9) platelets; IQR 392 to 598; P = 0.035). PFA closure time and PF4 increased significantly in patients without L(A)-alleles. Paroxetine 20 mg day(-1) does not increase overall bleeding time, but impairs platelet function by decreasing the levels of platelet serotonin and platelet ss-TG. These paroxetine effects appear to be mediated by 5-HTTLPR, with most pronounced effects in patients without L(A)-alleles.