p53 and the prostate-cancer-susceptibility gene RNASEL are tumour suppressor genes involved in apoptosis. We have previously reported that the common, functionally different variants Arg72Pro in p53 and Arg462Gln in RNASEL are associated with the age of disease onset of colorectal cancer in Lynch syndrome patients. To assess the combined effect of both variants, we screened 246 unrelated Lynch syndrome patients with a pathogenic germline mutation either in MSH2 (n = 138) or in MLH1 (n = 108) and colorectal cancer as first tumour, and 245 healthy controls. The global log rank test revealed significant differences in the age of disease onset for the genotypes of each variant (p = 0.0176 for p53 and p = 0.0358 for RNASEL) and for the combined genotypes of both variants (p = 0.0174). The highest difference in median age of disease onset was seen between homozygotes for the wild-types in both genes (42 years [range 22-75]) and homozygotes for the variant alleles in both genes (30 years [range 26-47]). A multivariate Cox regression model indicated that only the p53 and RNASEL genotypes had a significant influence on age of disease onset (p = 0.016 for p53 and p = 0.014 for RNASEL) in an additive mode of inheritance, and that the effects of both variants are purely additive, which supports the notion that the p53 and RNaseL pathways do not interact. These findings may be relevant for preventive strategies in Lynch syndrome.