Tolerance to lethal ischemia can be induced in gerbils by prior subjection to non-lethal ischemia. The sequential changes og ubiquitin immunoreactivity in the hippocampi of gerbils subjected to non-lethal ischemia followed by lethal ischemia were investigated. The double-ischemic group was subjected to non-lethal ischemia followed by lehtal ischeima, the single-ischemic group was subjected to lethal ischemia, only, the sham-ischemic qroup was subjected to sham operation followed by lethal ischemia. The densities of the CA (Cornu ammonis) 1 neurons were assessed by hematoxylin-eosin staining. In the double-ischemic group, the extent of the neuronal damage was less than that in the single-ischemic and sham ischemic groups (both P<0.02) and half that in the control group (P<0.002). Ubiquitin immunoreactivity (UIR) disappeared once after lethal ischemia in all the ischemic group (P<0.002). Ubiquitin immunoreactivity (UIR) disappeared once after lethal ischemia in all the ischemic groups. In the single and sham ischemic groups, UIR never reappeared, whereas in the double-ischemic group, it recovered partially during the early postischemic period and almost completely in the surviving cells eventually. Non-lethal ischemia reduces the ischemic damage caused by subsequent lethal ischemia in the Cai neurons of gerbils, and ubiquitination is related to the damage reduction.