New immunomodulatory agents showed promising activity in brain metastases (BM). However, little is known about the inflammatory response in BM. New insights are needed to further guide the development of treatment strategies. We investigated 17 human autoptic tissue specimens of BM from breast cancer (n = 3), non-small cell lung cancer (NSCLC; n = 5), small cell lung cancer (n = 3) and melanoma (n = 6). Immunohistochemical staining for a comprehensive panel of 21 inflammation-associated markers was performed. Results were quantified by manual counting of the various cell populations in three areas of 0.5 mm(2) (intratumoral, peritumoral, control region). Profound microglia activation with marked peritumoral accumulation and some intratumoral infiltration of HLA-DR-positive microglia/macrophages was found. A high proportion of these cells showed strong immunoreactivity for phagocytosis associated markers and MHC class 1, while a smaller subgroup of cells expressed molecules involved in radical production. Only few B- and T-lymphocytes were observed in and around BM. The number of CD8-positive T-cells was not correlated to MHC class 1 expression on tumor cells and only a fraction of T-cells showed Granzym B expression. Melanoma BM had significantly less accumulation of peritumoral microglia than NSCLC BM. The inflammatory pattern was independent from treatment of patients with glucocorticoids or radiation. The inflammatory reaction to BM is mainly characterized by activation of microglia/macrophages and shows pronounced upregulation of markers involved in phagocytosis, but seem to be insufficient in activating adaptive immunity. Treatment strategies aimed at activating specific immunity may potentiate immune attack on tumor cells.