Background: Studies on the relation between thrombin activatable fibrinolysis inhibitor (TAFI) and arterial thrombosis have produced conflicting results.TAFI regulates fibrinolysis, but other roles of this inhibitor, including anti-inflammatory properties, have also been demonstrated. Design and Methods: We investigated the association between TAFI activity and the risk of myocardial infarction. Additionally, we studied the association of common single nucleotide polymorphisms in the TAFI gene with levels of the TAFI protein and risk of myocardial infarction.We included 554 men under 70 years old with a first myocardial infarction and 643 controls participating in the Study of Myocardial Infarctions Leiden (SMILE), a case-control study. Results: We found odds ratios (95% confidence intervals) of a first myocardial infarction of 2.4 (1.6–3.6), 3.2 (2.1–4.7) and 3.4 (2.3–5.1) for subjects whose TAFI levels were in the third, second and first quartiles (lowest TAFI levels), respectively, compared with the fourth quartile, after adjusting for arterial disease risk factors. The rare -438A and 1040T alleles were associated with lower, and the rare 505G allele with higher TAFI levels than the common alleles. Carriers of the -438A allele had an increased risk of myocardial infarction (odds ratio 1.6 (1.0–2.5) for AA; odds ratio 1.2 (0.9–1.5) for AG compared with GG). The other single nucleotide polymorphisms were not associated with myocardial infarction. Conclusions: Low TAFI activity levels are associated with increased risk of a first myocardial infarction in men. The results on the association between TAFI single nucleotide polymorphisms and myocardial infarction were inconsistent.