Acute promyelocytic leukemia (APL) is a highly curable leukemia characterized by life-threatening coagulopathy leading to hemorrhagic and thrombo-ischemic events. We analyzed the incidence, outcomes and risk factors of thrombo-ischemic events in a large series of 1,210 patients with newly diagnosed APL reported to the PETHEMA registry. Therapy consisted of ATRA and chemotherapy (AIDA-based). Median age of patients was 46 years (range 2-90 years). Fifty-eight patients (5%) did not start the AIDA regimen either because they were unfit for chemotherapy, or because of early death before initiating ATRA. A total of 195 (16%) patients developed thrombo-ischemic events, the most frequent being superficial-vein and/or central catheter-related (6.9%) followed by central nervous system (2.2%), deep-vein thrombosis (2.1%), pulmonary embolism (2.1%), acute myocardial infarction (1.6%), or other locations (1.2%). Thrombo-ischemic events mostly occurred at diagnosis and during induction (4.0% and 9.3%, respectively). Patients developing life-threatening thrombo-ischemic events (i.e., excluding superficial and/or catheter-related) at diagnosis / induction had a 31% early death rate. Prolonged activated partial thromboplastin time (aPTT), age >40 years, ECOG performance status >1, platelets >25x109/L, and absence of bleeding at presentation were independent risk factors for life-threatening thrombo-ischemic events. Using these variables (1 point each), we developed and validated the Thromb-On risk score, identifying a high-risk group (3-5 points). The Thromb-On risk score was validated in a cohort of 585 patients treated since 2017 with arsenic trioxide plus all-trans retinoic acid (ATRA) (<10x109 leukocytes) or according to the AIDA protocol (≥10x109 leukocytes). This study could help to improve prevention and management of life-threatening thrombo-ischemic events through risk-adapted guidance, potentially leading to a decrease in early mortality in APL.