Brain specimens from five immunocompromised patients with CNS toxoplasmosis were studied with immunostaining for toxoplasma antigens and electron microscopy. The tachyzoites or toxoplasma antigens were predominantly localized in walls of hypertrophic, often thrombosed, arteries and adjacent brain tissue at the hyperemic rims of centrally necrotic lesions. This study suggests that in CNS toxoplasmosis of immunocompromised hosts, the organisms primarily invade and spread along segments of small artery walls, causing hypertrophy of arterial walls, thrombotic occlusion of lumens, circumscribed but expansive ischemic necrosis, and extravasation of organisms. Rapid response to chemotherapy can be explained by this preferential parasitism to the arterial walls. Early definitive diagnosis on brain biopsy specimens can be attained by immunostaining.