The tumour suppressor p53 is one of the most commonly altered genes in colorectal cancer (CRC) development. Genetic alterations in p53 may therefore be associated with postulated lifestyle risk factors for CRC, such as red meat consumption. In the European Prospective Investigation into Cancer and Nutrition-Norfolk study, we examined whether detailed estimates of dietary and lifestyle factors measured at baseline related to later development of p53 mutations in CRCs. After 10-year follow-up, there were 185 incident CRCs of which 34% had somatic p53 mutations (p53+). We observed significantly higher mean intakes of alcohol, total meat and red meat, in the group with p53 mutations and advanced Dukes' stage disease (daily alcohol intake was 7 and 12 g for p53- and p53+ cases, respectively, P = 0.04; daily total meat intake was 69 and 100 g for p53- and p53+ cases, respectively, P = 0.03 and daily red meat intake was 39 and 75 g for p53- and p53+ cases, respectively, P = 0.01). Each 50 g/day increment in total meat intake was associated with having p53 mutations in cases with advanced Dukes' stages [odds ratio (OR): 3.43, 95% confidence interval (CI): 1.47-7.96]. Similarly, each 50 g/day increment in red meat intake was also significantly associated with having consistent p53 mutations in cases with advanced Dukes' stages (OR: 2.42, 95% CI: 1.18-4.96). These effects of total meat or red meat intake and advanced Dukes' stages were independent of age, sex, body mass index, smoking and alcohol intake. Furthermore, P values for interaction between daily total meat or red meat intake and Dukes' stages were statistically significant in multivariable models (Pinteraction < 0.001). Our results suggest that p53 mutations accelerate progression of CRC to advanced Dukes' stage in association with higher meat especially red meat intakes.