Abstract Background: Recent genome-wide case-control study provided strong evidence for association of the Lymphotoxin-a (LTA) gene with myocardial infarction (MI) in a Japanese population. We aimed to replicate this finding in three genetically diverse populations. Methods and Results: Studying Korean (479 cases vs. 158 controls) Japanese (568 cases vs. 683 controls), and German (849 cases vs.851 controls) populations, we could not replicate the original finding of association between the LTA-SNP (in intron 1 A252G) and MI (OR=1.14, P=0.61, 95%CI=0.72-1.79 OR=1.13, P=0.43, 95%CI=0.83-1.53; , OR=0.88, P=0.45, 95%CI=0.62-1.23; respectively for a recessive inheritance model). However, analyzing clinical phenotypes of the MI patients stratified by the LTA-SNP genotype, it was revealed that coronary atherosclerosis was significantly more severe in the GG genotype group as compared with that of other genotypes in the Korean and Japanese populations ( P=0.0009 and P=0.016 , respectively) and it was marginally significant in the German population (P=0.06). Another German MI patient population (n=407) was tested to specifically address this question and it was found again that the LTA genotype was correlated at the significance niveau with the severity of coronary atherosclerosis (P=0.048). Conclusion: In three genetically diverse populations, we failed to replicate the association between the LTA-SNP with MI. By contrast, a consistent deviation in distribution of severe coronary atherosclerosis among patients stratified by the LTA genotype was found in all populations. Thus, while variants of the LTA gene may affect the extent of coronary atherosclerosis, their relation to myocardial infarction remains less certain.