Acetyl-l-carnitine (ALCAR), an endogenous water soluble molecule, is synthesized in the brain and is involved in many aspects of neuronal activity, including metabolism and neuronal membrane formation and integrity. To determine ALCAR's neuroprotective effects, focal cerebral ischemia was induced using four models of middle cerebral artery occlusion (MCAO) and treatment with 0-400 mgkg ALCAR (i.p.) prior to MCAO. While acute doses were without effect, pretreatment with chronic ALCAR (400 mgkgday for five days) significantly reduced infarct size. Lower chronic ALCAR doses were not effective. Additionally, elevations in microdialysate glutamate post-MCAO were attenuated by ALCAR treatment.