The urokinase plasminogen activator receptor (uPAR) and its ligand (uPA) play an important role in cell migration and extracellular proteolysis. We previously described uPAR/uPA overexpression in the cerebrospinal fluid (CSF) and brain tissues of patients with human immunodeficiency virus (HIV)-related cerebral diseases. In this study, we examined uPAR/uPA expression by immunohistochemistry (IHC) in brains of HIV patients with opportunistic cerebral lesions and in HIV-positive/negative controls. uPAR was found in macrophages/microglia with the highest levels in cytomegalovirus (CMV) encephalitis, toxoplasmosis, and lymphomas; in cryptococcosis and progressive multifocal leukoencephalopathy (PML) cases, only a few positive cells were found and no positivity was observed in controls. uPA expression was demonstrated only in a few macrophages/microglia and lymphocytes in all the cases and HIV-positive controls without different pattern of distribution; no uPA immunostaining was found in cryptococcosis and HIV-negative controls. The higher expression of uPAR/uPA in most of the opportunistic cerebral lesions supports their role in these diseases, suggesting their contribution to tissue injury.