Background Emerging yet contrasting evidence from animal and human studies associates ischemic preconditioning with improvement of subsequent stroke severity, although long-term outcome remains unclear. The purpose of this study was to analyze how preceding cerebral ischemic events influence subsequent stroke severity and outcome. Methods and Results Data for this retrospective cohort study were extracted from ASTRAL (Acute Stroke Registry and Analysis of Lausanne). This registry includes a sample of all consecutive patients with acute ischemic strokes admitted to the stroke unit and/or intensive care unit of the Lausanne University Hospital, Switzerland. We investigated associations between preceding ischemic events (transient ischemic attacks or ischemic strokes) and the impact on subsequent stroke severity and clinical improvement within 24 hours, measured through National Institute of Health Stroke Scale, as well as 3-month outcome, determined through a shift in the modified Rankin Scale. Of 3530 consecutive patients with ischemic stroke (43% women, median age 73 years), 1001 (28%) had ≥1 preceding cerebral ischemic events (45% transient ischemic attack, 55% ischemic stroke; 31% multiple events). After adjusting for multiple prehospital, clinical, and laboratory confounders, admission stroke severity was significantly lower in patients preconditioned through a preceding ischemic event, but 24-hour improvement was not significant and 3-month outcome was unfavorable. Conclusions Preceding ischemic events were independently associated with a significant reduction in subsequent stroke severity but worsened long-term clinical outcome. These results, if confirmed by future randomized studies, may help design neuroprotective strategies. The unfavorable effect on stroke outcome is probably a consequence of the cumulative disability burden after multiple ischemic events.