Background: Realgar-Indigo naturalis formula (RIF) containing A 4S 4 as a major ingredient is an oral arsenic available in China. The efficacy of RIF on pediatric acute promyelocytic leukemia (APL) is comparable to arsenic trioxide (ATO). However, it remains to be explored that the effects of these two arsenicals on differentiation syndrome (DS) and coagulation disorder which are the two main life-threatening events in children with APL. Procedure: We analyzed 68 consecutive children with newly diagnosed APL involved in SCCLG-APL study (NCT02200978). Patients received all-trans retinoic acid (ATRA) on day 1 of induction therapy. ATO (0.16 mg/kg·d) or RIF (135 mg/kg·d) was administrated on day 5 after mitoxantrone on day 3 (non-high-risk group, NHR) or day 2-4 (high-risk group, HR). Results: The incidences of DS were 3.0% and 5.7% in ATO (n = 33) and RIF (n = 35) groups ( p = 0.590), and 10.3% and 0% in patients with and without differentiation-related hyperleukocytosis, respectively ( p = 0.04). The dynamic changes of WBC between the ATO and RIF groups were not statistically different. However, patients with high WBC counts or percentage of promyelocytes in peripheral blood tended to develop differentiation-related hyperleukocytosis. The improvement of coagulation indexes in the ATO and RIF groups had no statistical difference. Fibrinogen and prothrombin time had the quickest recovery rate. Conclusions: This study provides evidences that the incidence of DS and recovery of coagulopathy are similar whenever treating with RIF or ATO in children with APL.