Chronic rhinosinusitis (CRS) is increasingly viewed as an inflammatory condition of the sinonasal mucosa interacting with bacteria and/or fungi. However, factors conferring susceptibility to disease remain unknown. Advances in genomics offer powerful tools to explore this disorder. The goal of this study was to evaluate the effect of single nucleotide polymorphisms (SNP) on CRS in a panel of genes related to cysteinyl leukotriene metabolism. Severe cases of CRS and postal code match controls were recruited prospectively. A total of 206 cases and 200 controls were available for the present study. Using a candidate gene approach, five genes related to cysteinyl leukotriene metabolism were assessed. For each gene, we selected the maximally informative set of common SNPs (tagSNPs) using the European-derived (CEU) HapMap dataset. These SNPs are in arachidonate 5-lipoxygenase (ALOX5), arachidonate 5-lipoxygenase-activating protein (ALOX5AP), leukotriene C4 synthase (LTC4S), cysteinyl leukotriene receptor 1 (CYSLTR1) and cysteinyl leukotriene receptor 2 (CYSLTR2) genes. A total of 59 SNPs were genotyped to capture the common genetic variations within these genes. Three SNPs located within the ALOX5, CYSLTR1 and ALOX5AP genes reached the nominal p-value threshold (p < 0.05) for association with CRS. However, none of these SNPs resist multiple testing adjustment. While these initial results do not support that polymorphsims in genes assessed involved in the leukotriene pathways are contributing to the pathogenesis of CRS, this initial study was not powered to detect polymorphisms with relative risk of 2.0 or less, where we could expect many gene effects for complex diseases to occur. Thus, despite this lack of significant association noted in this study, we believe that validation with external populations and the use of better-powered studies in the future may allow more conclusive findings.