B16F10 murine metastatic melanoma in the tails of C57BL/6 mice after subcutaneous injection is a well-established model. However, the histologic progression from injected cells to established local growth of melanoma has not been studied systematically. We therefore have investigated the histologic changes and growth of B16F10 melanoma at the injection site over a six-week time period. One million B16F10 melanoma cells were injected subcutaneously into the dorsal aspect of tails of C57/BL6 mice. Mice were sacrificed at zero, 12, 24, 48, 72 and 96 hours, and at one, two, three, four, five and six weeks. Sections were stained with Hematoxylin and Eosin and immunostained with antibodies to S100. Beginning at time zero, melanoma cells were detected between the dermis and the myofascial bundle of the tail. At week four, distant metastases were clinically evident in the inguinal region, though injection site tumors did not become evident until week six. Histological analysis showed melanoma cells at the injection site at all time periods and no injection site tumor until week six. Indeed, the injection site tumors arose two weeks after distant metastases were clinically apparent. A progression of S100 positivity was also observed. S100 immunostaining was negative in all injection site of B16F10 cells until the cells underwent a morphologic change from small and monomorphic at the injection site, to large, pleomorphic cells at week six in the clinically evident injection site tumors. Inguinal metastases were also S100 positive at week four, though injection site cells were still S100 negative. We conclude that in this particular established model for melanoma, local growth at the injection site may occur after the development of regional metastases. This may prove to be a good model for investigation of local growth of tumor cells and their interaction with metastatic lesions.