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Background Growing evidence indicates the adverse effect of ultra-processed food (UPF) consumption. However, it remains unknown whether UPF consumption influences the risk of colorectal cancer (CRC) precursors, namely conventional adenomas and serrated lesions. Methods We drew data from the Nurses' Health Study, Nurses' Health Study II, and Health Professionals Follow-up Study, comprising 142 052 participants who had undergone at least 1 lower gastrointestinal endoscopy during follow-up. To handle multiple records per participants, we used multivariable logistic regression for clustered data to calculate odds ratios (OR) and 95% confidence intervals (CIs) of colorectal polyps in relation to cumulative average consumption of UPFs. All statistical tests were 2-sided. Results We documented 11 644 patients with conventional adenomas and 10 478 with serrated lesions during 18-20 years of follow-up. Compared with participants in the lowest quintile of UPF consumption, those in the highest quintile had an increased risk of conventional adenomas (OR = 1.18, 95% CI = 1.11 to 1.26) and serrated lesions (OR = 1.20, 95% CI = 1.13 to 1.28). Similar results were found for high-risk polyps (ie, advanced adenomas and ≥10 mm serrated lesions; OR = 1.17, 95% CI = 1.07 to 1.28). These associations were slightly attenuated but remained statistically significant after further adjusting for body mass index, Western dietary pattern score, or individual dietary factors (fiber, folate, calcium, and vitamin D). The results remained essentially unchanged after excluding processed meat from total UPF intake. Conclusions Higher consumption of UPFs is associated with an increased risk of CRC precursors. UPFs might be a modifiable target for early prevention of CRC. [ABSTRACT FROM AUTHOR]