Non-melanoma skin cancers (NMSCs) are the most common malignancy among US Caucasians. Using a population-based study of NMSC we found that oral steroid use is associated with nearly 6-fold elevated risk of squamous cell carcinoma among individuals with a common genetic variant in the steroid receptor (NR3C1) gene. Given the large numbers of individuals on immunosuppressive drug therapy for inflammatory disease, these findings have important implications for NMSC screening and prevention.