Objectives - To compare the results of clinical assessment and MRI with neuropathological findings in the diagnosis of HIV and cytomegalovirus (CMV) associated CNS disease. Methods - A retrospective study of 35 patients infected with HIV who were examined at necropsy between four and 70 (median 20) days after neurological assessment and MRI. Results - Of the 35 patients, 19 had diffuse white matter hyperintensity on T2 weighted MRI, six of whom also had focal lesions. Nine other patients had focal white matter lesions and seven had changes in cortical atrophy only. Necropsy in the 19 with diffuse white matter hyperintensity showed HIV leukoencephalopathy (HIVLEP) with encephalitis in 10, CMV encephalitis in three, both HIVLEP/HIV encephalitis and CMV encephalitis in one, lymphoma in three, and non-specific inflammation in two. Necropsy in the 16 other patients without diffuse white matter hyperintensity showed CMV encephalitis in six, HIV encephalitis (without HIVLEP) in two, CMV encephalitis and HIVLEP/HIV encephalitis in one, non-HIV associated abnormalities in five, herpes simplex encephalitis in one, and lymphoma in one. CMV DNA was detected in CSF of five of seven patients with CMV encephalitis and in two of two with CMV associated polyradiculopathy but without CMV encephalitis. Diffuse white matter hyperintensity on MRI had a sensitivity of 100%, a specificity of 66.6%, and a positive predictive value of 58% for diagnosis of HIVLEP. Conclusion - Diffuse white matter hyperintensity on MRI can be due to either HIV or CMV associated pathology or non-specific abnormalities.