This study is proposed based on our work showing that the diabetes drug Pioglitazone strongly inhibits growth of tissue cultured squamous cell carcinoma (SCC) of the skin. This occurs at concentrations readily achievable by oral administration of this drug using doses currently approved for the treatment of diabetes. In our study, we propose to enroll 40 non-diabetic adult subjects (18-80 yrs of age inclusive) with a documented clinical history of frequent occurrence of skin squamous cell cancer to receive Pioglitazone (Actos®,Takeda Pharmaceuticals). Each subject will receive usual care for all new tumors they develop while on study (i.e, excision and plastic repair). The study protocol will randomize (1:1) patients for 6 months of observation followed by 6 months of treatment (group 1) or 6 months of treatment with drug followed by observation for 6 months (to examine washout effects). The biopsy specimens collected on and off therapy will be examined to determine if they express AKR1C3, an enzyme we believe increases resistance of SCC to prostaglandin inflammatory mediators. We will also examine the histologic grade of the removed tumors and study whether Pioglitazone treatment can decrease the number of aggressive versus well differentiated tumors in study patients. This pilot study is designed to detect a statistically significant change in SCC tumor numbers but is not sponsored by the drug manufacturer. The data obtained will not be used to effect a change in the product label.