It has been suggested that subtle signs of early cerebral infarction on CT are important indicators of outcome and of the effect of thrombolytic treatment in acute ischaemic stroke. We studied these signs prospectively, in 260 patients with an anterior circulation stroke from a European-Australian randomised trial of lubeluzole in acute ischaemic stroke. Interobserver reliability was assessed by means of the chi statistic. The validity of the early signs was assessed by comparing the assessments of the first CT with another CT at 1 week after the onset of stroke, and with stroke outcome at 12 weeks. Each initial CT study was assessed by two of a group of five reviewers, who were blinded to each other's assessments and to the findings on the follow-up CT. The images were assessed twice, once without clinical information and again after disclosure of the side (left or right hemisphere) of the lesion. All reviewers were experienced clinicians with a special interest and training in vascular neurology and CT. The median time between stroke onset and the first CT was 3.2 h; 59% of the patients were imaged within 3 h and 77% within 6 h. More than half of the patients (52%) had a large middle cerebral artery territory (MCA) infarct on follow-up CT. Chance-adjusted interobserver agreement (chi) for any early infarct was 0.27 (95% confidence interval (CI): 0.15 to 0.39). Agreement (chi) on the extent of a middle cerebral artery (MCA) infarct and on the indication for treatment with recombinant tissue plasminogen activator (rt-PA) was fair: 0.37 and 0.35, respectively. Patients with early signs of an infarct of more than 1/3 of the MCA territory were more likely to have a large MCA infarct on follow-up CT (odds ratio 5.7, 95% confidence interval 2.8-11.5); the positive and negative predictive value of these signs was 81% and 57%, respectively. Chance-adjusted interobserver agreement on early, subtle signs of a large MCA territory infarct on CT by neurologists was thus no more than fair, and the accuracy of prediction of actual infarct size on the basis of these signs only moderate, under circumstances which resemble everyday clinical practice.