Insulin resistance is thought to mediate the association between obesity and colorectal neoplasia, but no prior studies have assessed stimulated insulin sensitivity as a risk factor for colorectal neoplasia. This prospective study examined the association between insulin sensitivity measured directly using the frequently sampled intravenous glucose tolerance test (FSIGT) and later risk of colorectal adenomas. Among participants with a range of glucose tolerance levels enrolled in the Insulin Resistance Atherosclerosis Study, colonoscopies were conducted on 600 participants ages >/=50 yr, regardless of symptoms, about 10 yr after the first FSIGT and 5 yr after the second. Multiple logistic regression analyses were used. Within this cohort, diabetes was not associated with colorectal adenoma risk [ approximately 10 yr prior to colonoscopy adjusted odds ratio (OR(adj)) 1.00; 95% confidence interval (CI), 0.62-1.62 or approximately 5 yr prior to colonoscopy OR(adj) 0.96; 95% CI, 0.62-1.50]. Among non-diabetic participants, insulin sensitivity was not associated with colorectal adenoma risk at either prior study visit [lowest vs. highest insulin sensitivity, approximately 10 yr prior to colonoscopy OR(adj) 0.93; 95% CI 0.50-1.71 and approximately 5 yr prior to colonscopy OR(adj) 0.74; 95% CI, 0.38-1.46]. These results suggest that factors other than insulin sensitivity mediate the relationship between obesity and colorectal neoplasia.