This is a single center open label feasibility pilot project based at the University of Rochester. 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). Patients followed in the University of Rochester Dermatology Clinic who have had greater than 3 or more SCCs treated in the past year, without contraindication for the use of pioglitazone, and are on a stable drug treatment regimen will be offered participation .The study has a cross-over design, so patients will be enrolled and randomized to one arm of two treatment protocols: 1) six months of usual care while documenting and characterizing any new tumors that occur followed by 6 months of pioglitazone treatment plus usual care for the next 6 months or 2) six months of pioglitazone treatment followed by 6 months off treatment receiving usual care. The second group will offer the opportunity to assess whether there is any persistent beneficial effect after pioglitazone treatment ends, while tumors from the first group that occur during the initial 6 months of usual care will be characterized by study parameters for comparison to tumors arising while on treatment. At the end of the one year treatment period, the number of biopsy-proven new tumors that patients develop while taking pioglitazone will be counted and compared with the number that patients developed during the 6 month period they were not receiving treatment as well as the numbers that occurred during the 6 months after treatment (washout effect). This information will be used as the basis for a larger multicenter study. 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.