Context Myocardial infarction (MI) is the leading cause of death in the world. Variants in the 5-lipoxygenase-activating protein (FLAP) gene are associated with risk of MI.Objective To determine the effect of an inhibitor of FLAP on levels of biomarkers associated with MI risk.Design, Setting, and Patients A randomized, prospective, placebo-controlled, crossover trial of an inhibitor of FLAP (DG-031) in MI patients who carry at-risk variants in the FLAP gene or in the leukotriene A(4) hydrolase gene. Of 268 patients screened, 191 were carriers of at-risk variants in FLAP (87%) or leukotriene A4 hydrolase (13%). Individuals were enrolled in April 2004 and were followed up by designated cardiologists from a university hospital in Iceland until September 2004.Interventions Patients were first randomized to receive 250 mg/d of DG-031, 500 mg/d of DG-031, 750 mg/d of DG-031, or placebo. After a 2-week washout period, patients received DG-031 if they had received placebo first or placebo if they had received DG-031 first. Treatment periods lasted for 4 weeks.Main Outcome Measures Changes in levels of biomarkers associated with risk of MI.Results In response to 750 mg/d of DG-031, production of leukotriene B-4 was significantly reduced by 26% (95% confidence interval [CI], 10%-39%; P=.003) and myeloperoxidase was significantly reduced by 12% (95% Cl, 2%-21%; P=.02). The higher 2 doses of DG-031 produced a nonsignificant reduction in C-reactive protein (16%; 95% Cl, -2% to 31 %; P=.07) at 2 weeks. However, there was a more pronounced reduction (25%; 95% Cl, 5%-40%; P=.02) in C-reactive protein at the end of the washout period that persisted for another 4 weeks thereafter. The FLAP inhibitor DG-031 was well tolerated and was not associated with any serious adverse events.Conclusion In patients with specific at-risk variants of 2 genes in the leukotriene pathway, DG-031 led to significant and dose-dependent suppression of biomarkers that are associated with increased risk of MI events.