ABSTRACT: Smoking and ultra-processed foods (UPFs), a substantial part of the western diet, have been suggested to have a potential carcinogenic effect, though epidemiologic data are lacking. We aimed to examine the association between high UPF intake and colorectal adenomas, and to test the interaction with smoking. In a case-control study among consecutive subjects undergoing colonoscopy in a tertiary center during 2010-2015, UPF intake and smoking were compared between cases with colorectal adenomas and controls. Within 652 participants (cases, n = 294 and controls, n = 358), high UPF intake (defined as percent of kcal from UPF above the study sample upper tertile) was positively associated with adenomas (Odds ratio (OR) = 1.75, 95% Confidence interval (CI) 1.14-2.68), advanced and proximal adenomas (OR = 2.17, 1.29-3.65 and OR = 2.38, 1.37-4.11) among the whole study sample; and with adenomas (OR = 3.54, 1.90-6.61), non-advanced adenomas (OR = 2.60, 1.20-5.63), advanced adenomas (OR = 4.76, 2.20-10.30), proximal adenomas (OR = 6.23, 2.67-14.52), and distal adenomas (OR = 2.49, 1.21-5.13) among smokers. Additionally, a dose-dependent association was observed between tertiles of UPF intake and adenomas only among smokers (p for trend < 0.001). A significant interaction between smoking and high UPF intake was detected (p for interaction = 0.004). High intake of UPFs is strongly and independently associated with colorectal adenomas, especially advanced and proximal adenoma, and interacts with smoking. Results highlight smokers as more susceptible to the negative health effects of UPF consumption on colorectal neoplasia.