Background <p>Globally, poor diet is responsible for about 8 million deaths for non-communicable diseases, including cancers, in 2019. One strategy to promote healthier choices by informing consumers about food nutritional properties is the Front-Of-Pack Nutrition Labels, like Nutri-Score. Our study investigated the association between the updated Nutrient Profiling System (uNS-NPS), underlying Nutri-Score, and Colorectal Cancer (CRC) risk.</p> Methods <p>Data from two hospital-based case-control studies were used. Cases were CRC patients, while controls were individuals admitted for acute non-neoplastic conditions. Dietary habits were assessed via a validated food frequency questionnaire. The uNS-NPS dietary index (uNS-NPS-DI) was derived as the weighted average of the uNS-NPS scores of every food/beverage, for the energy intake provided by that food/beverage. Logistic regression models were employed to estimate the odds ratios (OR) and the corresponding 95% confidence intervals (CI) for the association between uNS-NPS-DI (as continuous and as categorical variable, based on quartiles of its distribution among controls) and CRC risk, adjusting for known risk factors.</p> Findings <p>A total of 2419 cases and 4723 controls were analysed. uNS-NPS-DI distribution (median 6.14, IQR: 5.17–7.15) was similar between cases and controls. Individuals in the highest quartile of uNS-NPS-DI (i.e. with the lowest nutritional quality of their diet) compared to those in the lowest showed a higher CRC risk (OR 1.17, 95% CI: 1.01–1.36).</p> Conclusions <p>A diet with low nutritional quality as measured by the uNS-NPS was modestly associated with increased CRC risk.</p>