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Some studies suggest that blood pressure (BP)-lowering effects of commonly used antihypertensive drugs differ among ethnic groups. However, differences in the response to second-line therapy have not been studied extensively.In the BP-lowering arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-BPLA), BP levels of European (n = 4,368), African (203), and South-Asian- (132) origin patients on unchanged monotherapy (atenolol or amlodipine) and/or on second-line therapy (added thiazide or perindopril) were compared. Interaction between ethnicity and BP responses (defined as end BP minus start of therapy BP) to both first- and second-line therapies were assessed in regression models after accounting for age, sex, and several other potential confounders.BP response to atenolol and amlodipine monotherapy differed among the three ethnic groups (interaction test P = 0.05). Among those allocated atenolol monotherapy, black patients were significantly less responsive (mean systolic BP (SBP) difference +1.7 (95% confidence interval: −1.1 to 4.6) mmHg) compared to white patients (referent). In contrast, BP response to amlodipine monotherapy did not differ significantly by ethnic group. BP responses to the addition of second-line therapy also differed significantly by ethnic group (interaction test P = 0.004). On adding a diuretic to atenolol, BP lowering was similar among blacks and South-Asians as compared to whites (referent). However, on addition of perindopril to amlodipine, BP responses differed significantly: compared to whites (SBP difference −1.7 (−2.8 to −0.7) mmHg), black patients had a lesser response (SBP difference 0.8 (−2.5 to 4.2) mmHg) and South-Asians had a greater response (SBP difference −6.2 (−10.2 to −2.2) mmHg).We found important differences in BP responses among ethnic groups to both first- and second-line antihypertensive therapies.