Effective eradication of established tumor and generation of a lasting systemic immune response are the goals of cancer immunotherapy. The objective of this phase IB study was to assess the safety and toxicity of treatment to metastatic tumor underlying the skin with the DNA encoding interleukin-12 (IL-12). This treatment strategy allowed the patient's own tumor to serve as a source of autologous antigen in the tumor microenvironment. We proposed that IL-12 protein produced by the transfected cells would result in the generation of both a local and systemic antitumor response. The tumor was treated with either three or six intratumoral injections of plasmid containing IL-12 DNA. This treatment strategy resulted in no significant local or systemic toxicity. The treatment did not result in an increase in serum IL-12 protein. The size of the treated lesion decreased significantly (greater than 30%) in five of the 12 patients. However, nontreated subcutaneous lesions or other disease did not decrease in size.