Neuropathological observations were made in 200 clinically suspected cases of bovine spongiform encephalopathy (BSE) in which pathognomonic vacuolar changes were absent. Routine histological and immunocytochemical techniques were applied to formalin-fixed, paraffin-embedded sections of the central nervous system. Significant neuropathological findings were detected in 85 (42.5 per cent) cases. The most frequent lesion, detected in 46 (23 per cent) cases, was a focal white matter vacuolation principally affecting the substantia nigra, but its clinical significance was unclear. Listeriosis was diagnosed in 17 (8.5 per cent) cases. In three of seven cases of non-suppurative encephalitis, lesions suggested sporadic bovine encephalomyelitis, a disease not previously reported in the UK. Suppurative thromboembolic or granulomatous lesions accounted for other inflammatory changes. Neuroectodermal tumours were present in five cases (2.5 per cent); three were identical in form and considered to be atypical ependymoma. Cerebrocortical necrosis, oedema or both were detected in four cases. The remaining cases (4.5 per cent), comprised those in which the changes were minor and of doubtful significance. Incidental pathological findings included occasional degenerating or vacuolated neurones, which occurred in the red nucleus in 105 brains, in the habenular nucleus in 71 brains, and singly at other sites in 17 brains. In sections of 37 brains immunostained with antiserum to prion protein (PrP), no evidence of PrP accumulation was found, providing some evidence that the series did not contain bovine prion disease cases which, based on the histological diagnosis, had given a false negative result. It is suggested that, of 115 cases (57.5 per cent) which lacked significant histological lesions, some were suffering from metabolic disorders. The study identified diseases and lesions which feature in the differential diagnosis of BSE. Their more accurate diagnosis may become particularly important if, as predicted, the BSE epidemic declines. © 1993, Academic Press Limited. All rights reserved.