We developed a diet and lifestyle score based on high sensitivity C-reactive protein (hsCRP), and investigated its association with odds of adenoma. We performed stepwise linear regression to develop the predicted hsCRP score among 23,330 participants in the Health Examinee Study and examined its association with colorectal adenoma among 1,711 participants in a cross-sectional study of colorectal adenoma. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) of colorectal adenoma using logistic regression models. Variances in hsCRP explained by body mass index were 61.1% in men and 64.5% in women in the prediction model. The increasing predicted hsCRP score was positively associated with colorectal adenoma (ORquartile 4 VS quartile 1 1.71, 95% CI: 1.12–2.62; Ptrend = 0.011 in men; ORquartile 4 VS quartile 1 2.86, 95% CI: 1.26–6.49; Ptrend = 0.019 in women). In subgroups, the associations differed by age and menopausal status among women, with stronger associations among women aged less than 50 years (OR≥median VS <median 3.74, 95% CI: 1.77–7.90, p for interaction 0.014) or premenopausal women (OR≥median vs <median 4.21, 95% CI: 2.12–8.36, p for interaction <0.001). The associations were more pronounced in the advanced or distal colon/rectum in men and in the advanced or proximal colon in women. The associations were attenuated after further adjustment for body mass index. In conclusion, we found that the predicted hsCRP score was positively associated with colorectal adenoma, suggesting that diet and lifestyle lowering inflammation may be a strategy to prevent colorectal neoplasia.