To compare clinicopathological findings in first and second passage chronic wasting disease (CWD(mule deer)) in cattle, six calves were inoculated intracerebrally with brain tissue derived from a first-passage CWD-affected calf in an earlier experiment. Two uninoculated calves served as controls. The inoculated animals began to lose both appetite and weight 10-12 months later, and five subsequently developed clinical signs of central nervous system (CNS) abnormality. By 16.5 months, all cattle had been subjected to euthanasia because of poor prognosis. None of the animals showed microscopical lesions of spongiform encephalopathy (SE) but PrP(res) was detected in their CNS tissues by immunohistochemistry (IHC) and rapid Western blot (WB) techniques. Thus, intracerebrally inoculated cattle not only amplified CWD PrP(res) from mule deer but also developed clinical CNS signs in the absence of SE lesions. This situation has also been shown to occur in cattle inoculated with the scrapie agent. The study confirmed that the diagnostic techniques currently used for diagnosis of bovine spongiform encephalopathy (BSE) in the US would detect CWD in cattle, should it occur naturally. Furthermore, it raised the possibility of distinguishing CWD from BSE in cattle, due to the absence of neuropathological lesions and to a distinctive multifocal distribution of PrP(res), as demonstrated by IHC which, in this study, appeared to be more sensitive than the WB technique.