Previous studies have shown that the recently injured brain has an increased sensitivity to subsequent brief episodes of severe ischemia. This investigation was designed to assess whether less severe secondary insults, which alone would be incapable of producing injury, exacerbate brain damage resulting from a primary episode of global ischemia. Rats were subjected to either 10 min of 2-vessel forebrain ischemia (primary insult alone), 20 min of hypotension (mean arterial pressure,MAP=either40or25mmHg) without vessel occlusion (secondary insult alone), or 10 min ischemia followed 1 h later by the hypotensive challenge (primary+secondary insult). Seven days later, the animals were neurologically evaluated and the brains then prepared for histologic analysis. Neither magnitude of secondary insult alone was found to produce injury. In contrast, the primary insult alone caused moderate damage in the hippocampus, caudoputamen and neocortex. With the exception of increased neuronal necrosis in the hippocampal CA1 sector in rats receiving the primary + secondary insult (MAP= 25mmHg), no worsening of outcome could be attributed to the secondary insults. These results indicate that the recovering brain may not be as sensitive to hypoperfusion as has previously been suggested.