Tryptophanyl-tRNA synthetase (WARS) gene polymorphisms have been associated with the patho-physiology of vascular angiogenesis and homeostasis. Data from a recent genome-wide linkage analysis suggested a potential role of WARS in the risk of myocardial infarction. However, no genetic-epidemiological data are available. From a prospective cohort of 14,916 initially healthy American men, we evaluated five common polymorphisms within or close to the WARS locus, all with a minor allele frequency >0.10, amongst 386 individuals who subsequently developed myocardial infarction and 386 matched individuals who remained free of reported cardiovascular events during follow-up. The polymorphisms were: a G > C substitution in the 5'-flanking region (dbSNP rs2273804), an A > G substitution in intron 1 (dbSNP rs941931), a 335T > C substitution in exon 10 (dbSNP rs9453), a C > T substitution in intron 10 (dbSNP rs1570305), and a C > T substitution in the C14orf68 region (dbSNP rs3736951). The observed genotypes were in Hardy-Weinberg equilibrium in the control group. Genotype- and haplotype-frequency distributions were similar between cases and controls. Further investigation using a haplotype-based matched logistic regression analysis, adjusting for age, smoking, randomized treatment-assignment (likelihood ratio test: chi(3)(2) = 3.20, p = 0.36) or with additional adjustment for BMI, hypertension, and diabetes (likelihood ratio test: chi(3)(2) = 2.38, p = 0.50) yielded similar null findings. An alternative haplotype analysis based on evolutionary arguments again yielded null results. In conclusion, we found no evidence for an association between the common polymorphisms or haplotypes of the tryptophanyl-tRNA synthetase gene tested and risk of myocardial infarction.