Background: Epidemiologic and animal studies suggest that selenium may reduce risk of colorectal cancer. However, the epidemiologic data is mainly from relatively small investigations, limiting their interpretation. Although substantial evidence suggests that smoking is a strong effect modifier for other antioxidative nutrients, little is known about smoking-selenium interactions in colorectal tumors. Methods: We studied the association of serum selenium and advanced colorectal adenoma, a cancer precursor, in 758 cases and 767 sex- and race-matched controls, randomly selected from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cases had at least one verified advanced adenoma (≥1 cm or villous elements, or high-grade dysplasia) of the distal colon, and controls had a negative sigmoidoscopy. Results: The multivariable odds ratio (OR) comparing participants in the highest quintile of serum selenium with those in the lowest quintile was 0.76 [95% confidence interval (95% CI), 0.53-1.10; Ptrend = 0.01]. The inverse association between serum selenium and advanced colorectal adenoma was significant among recent smokers (OR, 0.53; 95% CI, 0.27-1.01 for highest versus lowest tertile; P trend = 0.008). Serum selenium was unrelated to adenoma risk in nonsmokers and former smokers who quit smoking ≥10 years ago. Conclusion: Selenium may reduce the risk of developing advanced colorectal adenoma, particularly among the high-risk group of recent smokers.