Stressful, preconditioning stimuli can elicit rapid and delayed forms of tolerance to ischemic injury. The identification and characterization of preconditioning stimuli that are effective, but relatively benign, could enhance the clinical applicability of induced tolerance. This study examines the efficacy of brief hypothermia as a preconditioning stimulus for inducing rapid tolerance. Rats were administered hypothermic preconditioning or sham preconditioning and after an interval of 20-120 min were subjected to transient focal ischemia using a three-vessel occlusion model. The volume of cerebral infarction was measured 24 h or 7 days after ischemia. In other experiments, the depth or duration of the hypothermic stimulus was manipulated, or a protein synthesis inhibitor (anisomycin) was administered. Twenty minutes of hypothermia delivered 20 or 60 (but not 120) min prior to ischemia significantly reduces cerebral infarction. The magnitude of protection is enhanced with deeper levels of hypothermia, but is not affected by increasing the duration of the hypothermic stimulus. Treatment with a protein synthesis inhibitor does not block the induction of rapid tolerance. Hypothermic preconditioning elicits a rapid form of tolerance to focal ischemic injury. Unlike delayed tolerance induced by hypothermia, rapid tolerance is not dependent on either de novo protein synthesis or the duration of the preconditioning stimulus. These findings suggest that the mechanisms underlying rapid and delayed tolerance induced by hypothermia differ fundamentally. Brief hypothermia could provide a rapid means of inducing transient tissue protection in the context of predictable ischemic events.