Repetitive ischemia may result in more severe damage than a single similar duration insult. Inter-ischemic hypothermia significantly decreases this damage. It is unclear if protection would be evident if cooling was delayed until after the repeated insults. In this study, we evaluated the effects of 3 h of mild cooling (34-35 degrees C) beginning immediately after the third insult of ischemia, 0.5 h after the third insult and 1 h after the third insult in a gerbil model of repetitive ischemia. Neuronal damage was assessed in the cerebral cortex (CTX), hippocampus (CA1, CA4), striatum (STR), thalamus (THL), medial geniculate nucleus (MGN), and the substantia nigra reticulata (SNr). A '4-point' damage scale was used and evaluation was done in a blinded way. Group comparisons were done using the Mann-Whitney U-test for significance between the control and hypothermic groups. Immediate hypothermia after the third ischemic insult produced a significant protection in the CTX (P < 0.05), hippocampus (CA1 and CA4, P < 0.01), STR (P < 0.001), SNr (P < 0.01), MGN (P < 0.01) and THL (P < 0.01). Cooling at 0.5 and 1 h after the third insult produced no protection when compared to ischemic controls. The window of opportunity with hypothermia is narrow in repetitive ischemia. To be effective, therapy must be initiated as soon as possible after ischemic insults.