Spreading depolarizations (SD) occur in high frequency in patients with malignant hemispheric stroke (MHS). Experimentally, SDs cause marked increases in glutamate and lactate, whereas glucose decreases. Here, we studied extracellular brain glutamate, glucose, lactate, pyruvate and the lactate/pyruvate ratio in relationship to SDs after MHS. We inserted two microdialysis probes in peri-infarct tissue at 5 and 15 mm to the infarct in close proximity to a subdural electrode strip. During 2356.6 monitoring hours, electrocorticography (ECoG) revealed 697 SDs in 16 of 18 patients. Ninety-nine SDs in electrically active tissue (spreading depressions, SDd) were single (SDds) and 485 clustered (SDdc), whereas 10 SDs with at least one electrode in electrically inactive tissue (isoelectric SDs, SDi) were single (SDis) and 103 clustered (SDic). More SDs and a significant number of clustered SDs occurred during the first 36 h post-surgery when glutamate was significantly elevated (>100 mu M). In a grouped analysis, we observed minor glutamate elevations with more than two SDs per hour. Glucose slightly decreased during SDic at 5 mm from the infarct. Directions of SD-related metabolic changes correspond to the experimental setting but the long sampling time of standard microdialysis precludes a more adequate account of the dynamics revealed by ECoG.