Objective To analyze the comprehensive influencing factors for occurrence of differentiation syndrome (DS) in the patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all-trans retinoic acid (ATRA). Methods A total of 84 patients with freshly diagnosed APL and receiving induction treatment with ATRA in combination with arsenic trioxide (ATO) or anthracycline anticancer drugs in our department from 2005 to 2014 were enrolled in this study. According to the description of DS by Frankel, the subjects were divided into DS group (n＝35) and non-DS (normal) group (n＝51). Data were collected based on the potential risk factors. Univariate analysis and logistic regression analysis were used to study the risk factors for the occurrence and development of DS. Results The results of logistic regression analysis showed that white blood cell (WBC) count on initial diagnosis and genotype of promyelocyte leukemia-retinoic acid receptor alpha (PML-RARa) were independent risk factors for DS in APL patients (P＜0.05). Then chi-square analysis was carried out on these 2 items to exclude the mutual influence among multiple factors. The results indicated that there were significant differences in the WBC count on initial diagnosis and genotype of PML-RARa between the 2 groups (P＜0.05). Further chi-square analysis showed that type long (L) isoforms of PML-RARa was more significant than type short (S) isoforms of PML-RARa in the occurrence and development of DS. Conclusion WBC ≥10×109/L on initial diagnosis and carrying type L isoforms of PML-RARa are risk factors for DS in APL patients undergoing induction therapy with ATRA.