The purpose of this study was to determine whether the growth of human melanoma cells in the brain parenchyma is selective and represents the growth of unique cells. Six human melanoma cell lines derived from cutaneous lymph node or brain metastases (from six different patients) and melanoma cells isolated from fresh surgical specimens of two primary cutaneous melanomas, two lymph node metastases and two brain metastases (each from a different patient) were injected into the subarachnoid space of nude mice. All melanomas produced growths in the leptomeninges, but only melanoma cells isolated from brain metastases infiltrated into and grew in the brain parenchyma of nude mice. The results from in vitro assays for cell motility or production of gelatinase activity did not correlate with in vivo growth pattern. However, the in vitro growth of human melanoma cells in the presence of TGF-beta 2 inversely correlated with potential for brain parenchyma metastasis, i.e. the growth of cells from brain metastases was least inhibited by TGF-beta 2. These data suggest that melanoma brain parenchyma metastases are produced by unique cells that may be resistant to the antiproliferative effects of TGF-beta 2.