Squamous Cell Carcinoma (SCC) accounts for about 20% of skin cancer and occurs mainly on sun-exposed surfaces, although with a slightly different distribution to BCC. For example, SCC is relatively more common on the ears, hands, arms, and legs than BCC. Unlike BCC, SCC usually arises from an actinic keratosis (AK), a reddish, crusting, precancerous lesion also related to UV exposure. AKs may occur at a relatively young age, and can take years to develop. About 1 in 20 AKs will transform into SCC over 20 years, and the presence of AKs identifies persons who are likely to develop skin cancer.

SCC is almost 100% curable when treated early, but in later stages can become extremely dangerous, not only invading locally, but metastasizing to other parts of the body. About 2% of skin SCCs ultimately lead to death, or about 2,000 deaths per year in the United States.