Background and Purpose— The recent finding that genetic variation in the leukotriene biosynthesis pathway may confer an increased risk of ischemic stroke and atherosclerosis has implicated the leukotriene family as potential mediators of cardiovascular disease. Using a 2-stage replication design, we have examined whether polymorphisms in 8 genes related to this pathway are associated with early atherosclerosis and remodeling as measured by carotid artery intima-media thickness. Methods— We assessed 969 individuals from the Carotid Atherosclerosis Progression Study (CAPS), a community based study of normal subjects, for 39 variants in the leukotriene pathway. Significant associations and gene–environment interactions were found for 21 variants in the initial cohort and were examined in the next 1905 consecutive cases from the same CAPS population. Results— No replicable association between any individual polymorphism and carotid intima-media thickness itself was present after correction for multiple testing. A single gene–environment interaction was replicated between rs17222814 on bifurcation intima-media thickness and alcohol consumption exceeding 30 grams per day. Conclusion— The genetic variants we examined in the leukotriene biosynthesis pathway have little effect on early atherosclerosis and remodeling risk as determined by carotid intima-media thickness. Our study cannot exclude them as being risk factors for more advanced stages in the atherosclerotic process.