The metabolic syndrome is associated with increased risk of diabetes and coronary heart disease. Although higher BMI and other related factors have been frequently associated with colorectal cancer, whether the metabolic syndrome is associated with the risk of colorectal cancer is unclear. We therefore assessed the association of the metabolic syndrome with the risk of colorectal cancer in a subsample of participants of the Women's Health Initiative who had repeated measurements of the components of the syndrome at baseline and during follow-up. Women with diabetes at baseline enrollment were excluded. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) at baseline and in time-dependent analyses. Among 4862 eligible women, 81 incident cases of colorectal cancer were identified over a median follow-up of 12 years. Presence of the metabolic syndrome at baseline was associated with increased risk of colorectal cancer (HR 2.15, 95% CI 1.30–3.53) and colon cancer (HR 2.28, 95% CI 1.31–3.98). These associations were largely explained by positive associations of serum glucose and systolic blood pressure with both outcomes. Time-dependent covariate analyses supported the baseline findings. Our results suggest that the positive association of the metabolic syndrome with risk of colorectal cancer is largely accounted for by serum glucose levels and systolic blood pressure. The biological mechanism underlying these associations remains to be clarified.