The Realgar-Indigo Naturalis formula (RIF) is a proprietary Chinese medicine, which is one of the important drugs in the treatment of pediatric acute promyelocytic leukemia (APL). However, the dose of RIF in clinical application is not uniform and the long-term effectiveness and safety of combining RIF with all-trans retinoic acid (ATRA) in a larger population of pediatric APL patients remains undocumented. We conducted a multicenter single-arm clinical trial (ChiCTR-OIC-16010014) in China. Individuals newly diagnosed with APL were treated with CCCG-APL-2017 protocol which is based on RIF and ATRA in consolidation. The event-free survival (EFS) and overall survival (OS) outcomes were evaluated. We recruited 200 patients diagnosed with APL. The six-year OS rate was 100% in the low-risk (LR) group and 97.6% in the high-risk (HR) group. The six-year EFS rate was 98.3% in the LR group and 97.6% in the HR group. Plasma levels of arsenic remained stable after the administration of RIF at a dosage of 60 mg/kg/d for seven days and returned to baseline levels within fourteen days after discontinuation of RIF administration, which is consistent with a concentration of 135 mg/d/kg. Furthermore, controlling white blood cells (WBC) to maintain levels at or below 30 × 109/L during induction therapy can decrease the incidence of induced differentiation syndrome (DS) or alleviate its symptoms. Our study demonstrated that the CCCG-APL-2017 protocol, which combines RIF with ATRA, is both effective and safe in treating children with APL.© 2025. The Author(s).