Myocardial infarction (MI) has become one of the leading causes of death in the world. Its pathogenesis includes chronic formation of plaque inside the vessel wall of the coronary artery and acute rupture of the artery, implicating a number of inflammation-mediating molecules, such as the cytokine lymphotoxin-α (LTA). Functional variations in LTA are associated with susceptibility to MI. Here we show that LTA protein binds to galectin-2, a member of the galactose-binding lectin family. Our case–control association study in a Japanese population showed that a single nucleotide polymorphism in LGALS2 encoding galectin-2 is significantly associated with susceptibility to MI. This genetic substitution affects the transcriptional level of galectin-2 in vitro, potentially leading to altered secretion of LTA, which would then affect the degree of inflammation; however, its relevance to other populations remains to be clarified. Smooth muscle cells and macrophages in the human atherosclerotic lesions expressed both galectin-2 and LTA. Our findings thus suggest a link between the LTA cascade and the pathogenesis of MI.