This study aims to assess the risk of high intensity focused ultrasound (HIFU) therapy on the incidence of distant metastases and to investigate its association with HIFU-elicited anti-tumor immunity in a murine melanoma (B16-F10) model. Tumor-bearing legs were amputated immediately after or 2 days following HIFU treatment to differentiate the contribution of the elicited anti-tumor immunity. In mice undergoing amputation immediately after mechanical, thermal, or no HIFU treatment, metastasis rates were comparable (18.8%, 13.3%, and 12.5%). In contrast, with a 2-day delay in amputation, the corresponding metastasis rates were 6.7%, 11.8%, and 40%, respectively. Animal survival rate was higher and CTL activity was enhanced in the HIFU treatment groups. Altogether, our results suggest that HIFU treatment does not increase the risk of distant metastasis. Instead, HIFU treatment can elicit an anti-tumor immune response that may be harnessed to improve the overall effectiveness and quality of cancer therapy.