Front-line treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) is superior to standard ATRA and chemotherapy (CHT) in patients with low-/intermediate-risk acute promyelocytic leukemia (APL). However, for high-risk (HR) patients (defined as those with a white blood cell count ≥ 10×10⁹/L), the role of ATRA-ATO is subject to debate, and study data are scarce. The objective for the present real-world cohort study was to assess the outcomes in 135 HR APL patients treated with ATRA-CHT or ATRA-ATO during induction at 12 French hospitals between 2010 and 2021. Of the 135 patients, 50 (37%) received ATRA-ATO as induction therapy (though combination with cytoreductive treatment was usually necessary), and 85 received standard ATRA-CHT ("CHT group"). The complete response rates were 90% in the ATRA-ATO group and 76% in the CHT group (p = 0.052). The five-year overall survival (OS) rate was significantly higher in the ATRA-ATO group (89.86% [95% confidence interval: 81.81-98.70]) than in the CHT group (72.69% [63.30-83.47]; p = 0.035). The combination of ATRA and ATO was effective and safe in this large, real-world cohort of HR APL patients. The forthcoming results of the APOLLO trial (a direct comparison of ATRA-ATO with ATRA-CHT) might validate our present findings.