Abstract The effects of ultrasonic shock waves (SW), recombinant interleukin-12 (rIL-12) protein and DNA plasmids coding for interleukin-12 (pIL-12) were investigated on progression of mouse B16 melanoma and RENCA renal carcinoma tumors. Tumor cells were implanted and grown on the hind legs of syngeneic mice. Before treatment, mice were anesthetized and the tumor region was shaved and depilated. Air bubbles at 10% of tumor volume and an equal volume of phosphate buffered saline (PBS), either with rIL-12 or pIL-12 were injected into the tumor. SW treatment consisted of 500 SWs (7.4-MPa peak negative pressure) from a spark-gap lithotripter. Tumor volume was measured every other day and tumor growth was statistically modeled. SW treatment augmented by air injection induced a tumor growth delay for a few days immediately after exposure. Intratumor rIL-12 injection enhanced the SW effect on tumor progression, to the extent that a statistically significant increase in survival was realized in both tumor models. pIL-12 injection alone, which is known to produce some gene transfer, provided no detectable tumor-growth reduction. The combination of SW and pIL-12 injection provided a statistically significant reduction in tumor growth relative to SW alone for both tumor models. IL-12 expression due to SW-induced gene transfer was confirmed in ELISA assays. This research demonstrates a potentiality for further development of ultrasound (US)-enhanced cancer gene therapy.