Objective:To study the predictive value of clinical criteria and polymerase chain reaction (PCR) assay of cerebrospinal fluid (CSF) for the diagnosis of cytomegalovirus (CMV)‐related neurological disorders during AIDS.Setting:Four infectious diseases departments in two tertiary referral teaching hospitals in Paris, France.Design and participants:One‐year prospective study involving 164 consecutive immunosuppressed HIV‐seropositive patients undergoing lumbar puncture (LP).Methods:A tentative diagnostic classification, based on strict operational criteria and PCR assay of CSF, was performed at the time of LP. At the end of the study, tentative diagnoses and PCR results were blindly and independently compared with the firm diagnoses, based on central nervous system histology, clinical outcome and/or viral culture of CSF.Results:The tentative diagnosis showed CMV‐related neurological disease in 38 patients, and CMV DNA was detected in 42. Among the 88 patients for whom a firm diagnosis was possible, 26 had a diagnosis of CMV‐related neurological disease. The concordance between the tentative and firm diagnoses was 61%, with a kappa index of 0.40. In contrast, the sensitivity and specificity of PCR were respectively 92 and 94%, with positive and negative predictive values of 86 and 97%. The presence of CMV DNA in CSF was associated with an increased risk of death (P< 0.0001).Conclusions:Unlike clinical criteria, PCR detection of viral DNA in CSF can be used reliably for antemortem diagnosis of CMV‐related neurological disease, a frequent complication of AIDS in this study. This rapid method should make a major impact on the management of these patients.