The National Polyp Study (NPS), a randomized clinical trial to evaluate effective surveillance of patients discovered to have one or more colorectal adenomas, was the framework for this statistical analysis which used a multiple logistic model to assess the independent risk factors of patient and polyp characteristics associated with high-grade dysplasia in adenomas. The database included 3371 adenomas from 1867 patients. Adenoma size and the extent of the villous component were found to be the major independent polyp risk factors associated with high-grade dysplasia (p < 0.0001). The adjusted odds ratios were 3.3 for medium-sized adenomas and 7.7 for large adenomas relative to small adenomas and 2.7 for villous A adenomas, 3.4 for villous B adenomas, and 8.1 for villous C and D adenomas relative to tubular adenomas. Increased frequency of high-grade dysplasia in adenomas located distal to the splenic flexure was attributable mainly to increased size and villous component rather than to location per se. The adjusted odds ratio was 1.4 (p < 0.11) for left-sided location. Multiplicity of adenomas affected the risk for high-grade dysplasia in patients but was dependent on adenoma size and villous component and was not an independent factor. The adjusted odds ratio was 1.3 (p < 0.17) for multiplicity. Increasing age was associated with risk for high-grade dysplasia in patients, and this effect was independent of the effect of adenoma size and histological type. The adjusted odds ratio was 1.8 (p < 0.0016) for age ≥60 yr. Gender was not associated with high-grade dysplasia. The adjusted odds ratio was 1.0 (p < 0.95) for men. The size of the patient series, the prospective nature of the data collection, the completeness of information on all patients, the requirements of complete examination of the entire colon and pathological examination of all lesions encountered, and the exclusion of patients with previously diagnosed adenomas are, collectively, features unique to this study. The detailed model provided by the analysis integrates multiple patient and adenoma factors associated with high-grade dysplasia in colorectal adenomas.