BACKGROUND Detailed histopathologic studies of melanomas occurring in neonatal Sinclair miniature swine have demonstrated a remarkable similarity to human melanoma. A significant difference is the predictable, complete regression of primary and metastatic tumors that occurs in all animals by early adulthood (1 to 2 years). Prior histopathologic descriptions of regression in this model have been incomplete with regard to the time of onset and chronologic sequence of events. This lack of data makes it difficult to plan studies of regression mechanisms especially when requiring the harvesting of tumor tissue. METHODS By routine histologic methods, 94 tumors from 46 piglets were evaluated for the degree of regression, presence of pigment-laden macrophages, and presence of lymphocytes. One or more punch biopsies were performed on 51 tumors before excision, for a total of 256 biopsies. RESULTS Regression took place in two phases. The first phase began during the 4th week after birth; was preceded by a rapid, massive infiltration of pigment-laden macrophages; and was most active during the 2nd month. Significant numbers of lymphocytes were rarely seen in tumors during this phase of regression. In the vast majority of tumors, this initial regression activity was followed by regrowth of residual tumor usually appearing as emerging clones (intralesional transformation). The second phase of regression was characterized by asymmetrically distributed lymphocytic infiltration of the residual melanoma, and progressive regression of tumor over several months. Significant numbers of lymphocytes were not present in the majority of the tumors until the beginning of the 4th month. CONCLUSIONS We conclude that regression of melanoma in this animal model is a complex event in which the immune system participates differentially during the natural history of the disease.