The potential for enhancement of the metastatic spread of cells from mouse melanoma tumors was examined for exposure to diagnostic ultrasound (DUS) and high-amplitude ultrasound (HAUS) without and with ultrasound (US) contrast agent. The melanoma cell line B16-D5, which is metastatic specifically to lung, was cultured and implanted on a hind leg of female C57/bl6 mice. For DUS, tumors were scanned using 1.5-MHz harmonic B-mode imaging with 1-Hz intermittent frame triggering at 2.1 MPa (equivalent MI = 1.7) in a 37 degrees C water bath. For HAUS, a 1.35-MHz focused transducer directed 1-ms bursts at 5 MPa to the tumor at a 1-Hz rate. A total dose of 1 mL/kg Optison was injected during exposures. Exposure without contrast agent received the same exposure followed by the contrast agent with the US off. The primary tumor was removed surgically one day after US. Lungs were removed after four weeks for evaluation of metastases. Experiments involved exposure without and with contrast agent in groups of 20 mice. For DUS, mean counts of 0.8 +/- 0.3 (standard error) and 1.3 +/- 0.9 (P = 0.62) metastases were found for groups exposed without and with contrast, respectively. For HAUS, mean counts of 3.4 +/- 1.2 and 5.9 +/- 1.7 (P = 0.35) metastases were found for groups exposed without and with contrast, respectively. The lack of effect of DUS exposure with contrast confirms a previous finding. However, the HAUS counts and incidence were significantly larger than the DUS results (P < 0.05) in a two-way analysis of variance. This indicates a potential for HAUS to enhance metastasis.