Galectin-3 is a lectin involved in fibrosis, inflammation and proliferation. Increased circulating levels of galectin-3 have been associated with various diseases, including cancer, immunological disorders, and cardiovascular disease. To enhance our knowledge on galectin-3 biology we performed the first genome-wide association study (GWAS) using the Illumina HumanCytoSNP-12 array imputed with the HapMap 2 CEU panel on plasma galectin-3 levels in 3,776 subjects and follow-up genotyping in an additional 3,516 subjects. We identified 2 genome wide significant loci associated with plasma galectin-3 levels. One locus harbours the LGALS3 gene (rs2274273; P = 2.35 x 10(-188)) and the other locus the ABO gene (rs644234; P = 3.65 x 10(-47)). The variance explained by the LGALS3 locus was 25.6% and by the ABO locus 3.8% and jointly they explained 29.2%. Rs2274273 lies in high linkage disequilibrium with two non-synonymous SNPs (rs4644; r(2) = 1.0, and rs4652; r(2) = 0.91) and wet lab follow-up genotyping revealed that both are strongly associated with galectin-3 levels (rs4644; P = 4.97 x 10(-465) and rs4652 P = 1.50 x 10(-421)) and were also associated with LGALS3 gene-expression. The origins of our associations should be further validated by means of functional experiments.