Thus, to enhance our comprehension of the intricate molecular and cellular processes associated with high‐risk HPV co‐infection, we herein explored the synergistic effect of the E6/E7 oncoproteins of the two most common high‐risk HPVs (HPV16 and HPV18) in CRC cell models of diverse mutational backgrounds (namely KRAS and TP53 mutants). This evidence concerns the gene TP53 and colorectal carcinoma.