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). The gene discussed is KRAS; the disease is colorectal carcinoma.