The effect of mannitol on focal cerebral ischemia in cynomolgus monkeys was studied. After the implantation of a snare ligature about the right middle cerebral artery (MCA) and of deep electrodes for measurement of cerebral blood flow, unanesthetized animals underwent 4-hour MCA occlusion. Ten monkeys were untreated, and 12 animals received mannitol (1.2 g/kg i.v.) 20 minutes after occlusion. The preocclusion and postocclusion deep hemispheric cerebral blood flows (mean CBFs) were similar in the treated and untreated groups. Occlusion produced an average decrease in flow of about 50% in both groups. In the mannitol-treated group the mean CBF of 30.0 fell to 15.8 ml/100 g/minute, and in the untreated group the mean CBF of 29.5 fell to 12.5 ml/100 g/minute. Several animals showed increased CBF after mannitol treatment, and there was an average 21% increase in CBF in the mannitol group after treatment, but this was not a statistically significant difference from the untreated group. With regard to clinical status, there was no significant difference between the mannitol group and the untreated group after MCA occlusion. In individual animals, mannitol treatment caused no significant improvement. Two weeks after occlusion, brains were evaluated for infarct size; there was no significant difference between the mannitol and the untreated groups. In this study, treatment with mannitol (1.2 g/kg) 20 minutes after MCA occlusion failed to modify significantly the mean hemispheric CBF, clinical status, or the pathological effects of 4-hour focal cerebral ischemia.