Abstract Our previous studies identified a functional SNP, R952Q in the LRP8 gene, that was associated with increased platelet activation and familial and early-onset coronary artery disease (CAD) and myocardial infarction (MI) in American and Italian Caucasian populations. In this study, we analyzed four additional SNPs near R952Q (rs7546246, rs2297660, rs3737983, rs5177) to identify a specific LRP8 SNP haplotype that is associated with familial and early-onset CAD and MI. We employed a case–control association design involving 381 premature CAD and MI probands and 560 controls in GeneQuest, 441 individuals from 22 large pedigrees in GeneQuest II, and 248 MI patients with family history and 308 controls in an Italian cohort. Like R952Q, LRP8 SNPs rs7546246, rs2297660, rs3737983, and rs5177 were significantly associated with early-onset CAD/MI in both population-based and family-based association studies in GeneQuest. The results were replicated in the GeneQuest II family-based population and the Italian population. We then carried out a haplotype analysis for all five SNPs including R952Q. One common haplotype (TCCGC) was significantly associated with CAD (P=4.0×10−11) and MI (P=6.5×10−12) in GeneQuest with odds ratios of 0.53 and 0.42, respectively. The results were replicated in the Italian cohort (P=0.004, OR=0.71). The sib-TDT analysis also showed significant association between the TCCGC haplotype and CAD in GeneQuest II (P=0.001). These results suggest that a common LRP8 haplotype TCCGC confers a significant protective effect on the development of familial, early-onset CAD and/or MI.