Twenty cases of acute or early multiple sclerosis have been examined using staining, histochemical or immunocytochemical methods. They had died within 6 months after initial clinical onset (12) or commencement of an "anatomically-remote" acute relapse (8). Plaques in these acute cases showed the following characteristics: lymphocytic perivascular infiltration, plaque hypercellularity, plaque macrophage infiltration and intra-macrophage myelin debris. In most cases of clinical duration of less than 12 weeks, some macrophages showed characteristic formaldehyde-resistant markers for haematogenous macrophages (muramidase, anti-alpha 11-antitrypsin, MAC and HAM56) but, with the exception of the last, these markers subsequently declined indicating a haematogenous origin for macrophages in the early lesion. Lymphocytes were prominent in perivascular (perivenous) regions but, except in one case, were only scanty in or at the demyelinating edge of plaques. Oligodendroglial hyperplasia, indicative of remyelinating activity, was seen at the edge of plaques in one quarter of these acute cases (7 times the rate seen in chronic lesions). Astrocytic activation was not apparent in the earliest stages but was usually seen from about 6 weeks onwards. The conclusion from these observations is that the prime inflammatory process is around blood vessels with usually only scanty initial inflammatory activity in the parenchyma of the brain. Macrophages emigrating from blood vessels digest myelin either as a response to inflammatory damage to the myelin or as a response to activation signals produced in either the perivascular region or plaque.