Excessive and unprotected exposure to ultraviolet (UV) radiation from outdoor sunshine or indoor tanning lamps is the leading risk factor for developing squamous cell skin cancer (SCSC). UV radiation damages correct DNA sequences in squamous cells, and once DNA is damaged, there is a risk it will be improperly repaired, particularly with repeat damage and cumulative exposure. Since DNA damage accumulates over time, aging also increases the risk of SCSC, along with UV-induced damage during childhood and adolescence.

People who work outdoors or spend much of their leisure time outside are at risk, especially if they are unprotected from ultraviolet radiation, along with anyone who uses indoor tanning devices. Those who have a history of skin burns, trauma, or chronic inflammation are also at increased risk. Immunocompromised patients, particularly patients with a history of an organ transplant, are at significantly higher risk.

People with lighter-colored skin—especially those with sun-sensitive skin that freckles and burns quickly—are at the highest risk because they are more susceptible to UV damage. However, SCSC occurs among people of all skin complexions.

Rare genetic mutations, such as recessive dystrophic epidermolysis bullosa or xeroderma pigmentosum, can significantly increase the risk for aggressive SCSC formation. These genetic conditions impact the cell’s ability to repair DNA damaged by UV radiation.

Besides UV radiation, exposure to other agents contributes to SCSC risk. The 2023 International Agency for Research on Cancer lists arsenic, azathioprine, coal tar, cyclosporine, mineral and shale oils, soot, and X-ray or gamma radiation as carcinogenic agents that contribute to the development of nonmelanoma skin cancer.

Weakened immune systems put people at risk for SCSC, including immunosuppression following organ transplantation or infection with the human immunodeficiency virus. There is some evidence that viral infection with polyomaviruses or specific types of human papilloma viruses increases the risk for SCSC, particularly among people who are immunocompromised for other reasons. Health conditions like chronic lymphocytic leukemia or lymphoma will also suppress the immune system, increasing the risk for SCSC. Immunosuppression not only increases the risk of SCSC development, but recurrence, metastasis, and mortality.