COX-2 is upregulated in most colorectal cancers. Most of the COX-2 tumor-inducing effects are believed to be mediated through overproduction of prostaglandin E(2) (PGE(2)), which can be measured using a urinary metabolite of PGE(2), PGE-M. Urinary PGE-M was assessed in a case-control study of colorectal adenoma. Included in the analysis were 224 cases with at least one advanced adenoma, 152 cases with multiple small tubular adenomas, 300 cases with only a single small tubular adenoma, and 364 polyp-free controls. There were no statistical differences in PGE-M levels between controls and cases with a single small tubular adenoma. However, cases with either an advanced adenoma or multiple small tubular adenomas had more than 25% higher levels of PGE-M than controls. Participants with the highest quartile level of PGE-M were approximately 2.5-fold more likely to have advanced or multiple small tubular adenoma in comparison with those with the lowest level of PGE-M [OR = 2.53; 95% confidence interval (CI), 1.54-4.14; P(trend) < 0.001]. The association was strongest among women. PGE-M level was associated with increased risk for multiple or advanced adenoma but not single small adenoma. Our study suggests that PGE-M may be a useful risk marker for assessing the risk of harboring clinically more important versus less important colorectal neoplasia.