The effects of caffeine on ischemic neuronal injury were determined in rats subjected to forebrain ischemia induced by bilateral carotid occlusion and controlled hypotension (50 mmHg for 10 min). High resolution (100 microns) multi-slice, multi-echo magnetic resonance images were obtained daily for three consecutive days post-operatively in sham-operated rats and in rats that received either saline vehicle (controls), a single i.v. injection of 10 mg/kg caffeine 30 min prior to an ischemic insult (acute caffeine group), or up to 90 mg/kg per day of caffeine for three consecutive weeks prior to an ischemic insult (chronic caffeine group). Rats in the control group exhibited enhanced magnetic resonance image intensity in the striatum 24 h after ischemia which increased in the striatum and also appeared in the hippocampus after 48 h, and which began to resolve in both regions by 72 h post-ischemia. Histopathological analysis of each rat following the final magnetic resonance examination showed that ischemic neuronal injury was strictly confined to the brain regions showing magnetic resonance image changes. Acute caffeine rats showed accelerated changes in the magnetic resonance images, with increased hippocampal intensity appearing at 24 h post-ischemia. Although there was magnetic resonance evidence of accelerated injury, quantitative analysis of the histopathological data at 72 h showed no significant difference in the extent of neuronal injury in any brain region between control-ischemic and acute caffeine rats. Nine out of 11 rats in the chronic caffeine group showed no magnetic resonance image changes over the three study days. Chronic caffeine rats had significantly less neuronal damage in all vulnerable brain regions than either of the other groups of ischemic rats. The accelerated ischemic injury in rats treated with an acute dose of caffeine may occur secondary to antagonism of adenosine receptors, whereas protection from ischemic injury following chronic administration of caffeine may be mediated by up-regulation of adenosine receptors.