Numerous studies have indicated that exposure to nonsteroidal anti-inflammatory drugs is associated with a lowered risk of colorectal cancer. However, analyses of the effect of aspirin upon tumorigenesis in Apc(Min/+) mice have yielded contrasting results. We show that adult dietary exposure to aspirin does not suppress intestinal tumorigenesis in Apc(Min/+) mice, but that continual exposure from the point of conception does. To test whether this regime could suppress the phenotype of murine models of hereditary nonpolyposis colorectal cancer, Msh2-deficient mice were exposed to aspirin. This did not modify the mutator phenotype of Msh2(-/-) mice, but weakly extended survival. Finally, we analyzed (Apc(Min/+), Msh2(-/-)) mice and found that lifetime aspirin exposure significantly delayed the onset of both intestinal and mammary neoplasia. Thus embryonic and perinatal exposure to aspirin suppresses neoplasia specifically associated with the loss of Apc function, opening a potential window of opportunity for nonsteroidal anti-inflammatory drug intervention.