Objective— The purpose of this study was to test the association between polymorphisms in genes involved in either LDL cholesterol (LDL-C) metabolism or statin pharmacokinetics and LDL-C reduction with statins. Methods and Results— 49 tagging and candidate polymorphisms in 9 genes were genotyped in 1507 post-ACS subjects randomized to atorvastatin or pravastatin. Two polymorphisms (rs7412, rs429358) that define the ε2, ε3, and ε4 isoforms of apolipoprotein E were significantly associated with percent reduction in LDL-C with atorvastatin (ε2 carriers 53.8%, ε3/ε3 48.1%, and ε4 carriers 46.4%, respectively, P =0.00039) and replicated in the pravastatin arm (ε2 carriers 22.1%, ε3/ε3 21.8%, and ε4 carriers 16.6%, respectively, P =0.00038). The proportion of subjects achieving an LDL-C ≤70 mg/dL at day 30 was higher for ε2 than ε4 carriers ( P =1.3×10 −5 ). In the pravastatin group, the triallelic rs2032582 variant (G2677T/A) in ABCB1 was associated with the percent reduction in LDL-C (GG 23.3%, non-G heterozygote 20.3%, and non-G homozygote 17.4%, P =0.042). Conclusion— Carriers of APOE ε2 versus ε4 had significantly greater LDL-C reduction with atorvastatin and with pravastatin, and more frequently achieved a guideline-recommended LDL-C ≤70 mg/dL. Polymorphisms in triallelic G2677T/A variant in ABCB1 were associated with the degree of LDL-C lowering with pravastatin.