Background Candidate genes associated with cardiovascular disease (CVD) represent potential risk factors for the metabolic syndrome (MetS). Methods The association between prevalent MetS and a panel of 62 polymorphisms within 42 candidate genes, previously implicated in the pathophysiology of CVD, were investigated in 20,806 white participants of the Women's Health Study. All were free of known CVD and diabetes at baseline. Logistic regression was performed to investigate the relationship between genotype and the MetS assuming an additive model. Stratified analyses by hormone therapy use were also performed. Correction for multiple testing was performed using false discovery rate for polymorphisms and false positive rate probability for stratified analysis, respectively. Results The prevalence of the MetS was 23%. In a marker-by-marker analysis, the ADRB2 rs180088 (OR 1.22, 95% CI 1.01-1.48) and PAI1 rs1799768 (OR 1.05, 95% CI 1.01-1.10) were associated with an increased MetS risk, whereas the C5 rs17611 (OR 0.95, 95% CI 0.91-1.00) and the CTLA4 rs5742909 (OR 0.91, 95% CI 0.84-0.99) were associated with a decreased risk. In postmenopausal women, an increased MetS risk was found for the ADRB2 rs180088 (OR 1.28, 95% CI 0.99-1.65), PAI1 rs1799768 (OR 1.07, 95% CI 1.01-1.14), SCNN1A rs5742912 (OR 1.22, 95% CI 1.01-1.47), and IL1A rs1800587 (OR 1.07, 95% CI 1.01-1.15), whereas the AGTR1 rs5186 (OR 0.93, 95% CI 0.87-0.99) was associated with decreased risk. However, none remained significant after false discovery rate correction. In a stratified analysis, one or more copies of the variant C allele of SCNN1A rs5742912 were associated with an increased MetS risk among the current users (OR 1.56, 95% CI 1.21-2.01, P interaction .007, false positive rate probability 0.13). Conclusions Effect modification of the SCNN1A rs5742912 on the MetS by hormone therapy use warrants further investigation.