Arsenic trioxide (ATO) is an effective therapy for relapsed acute promyelocytic leukemia (APL) patients; however, the optimal treatment strategy remains unclear, and knowledge of the prognostic factors is still limited. We retrospectively analyzed the outcomes of 64 consecutive first relapsed APL patients (12 with molecular relapse and 52 with hematologic relapse). Patients received re-induction with intravenous ATO-based regimens. Patients who achieved a CR2 were offered further courses of alternating ATO/conventional chemotherapy with or without stem cell transplantation (SCT). With a median follow-up of 27 months (range, 6-57) in the molecular relapsed subgroup, the 3-year relapse-free survival (RFS) and overall survival (OS) rates were 81.5 % and 100 %, respectively. With a median follow-up of 38 months (range, 0-129) in the hematologic relapse group, the 3-year RFS and OS rates were 57.1 % and 72.1 %, respectively. Furthermore, in the hematologic relapse group, we compared the outcome between relapsed patients after previous ATO therapy (n = 20) with those who did not receive prior ATO therapy (n = 32). The CR2 rate was 80 % (16/20) vs. 93.8 % (30/32), (p = 0.189). However, the relapse rate was 68.8 % (11/16) vs. 33.3 % (10/30), (p = 0.03). The 4-year OS rate was 62.4 % vs. 71.2 %, (p = 0.816), and the 4-year RFS rate was 29.8 % vs. 66.2 % (p = 0.023). The results indicate that, irrespective of frontline therapy with ATO, salvage therapy with an ATO-based regimen remains effective. However, the long-term survival for those patients who received previous ATO-based treatment was inferior compared to those who did not receive prior ATO. In addition, the alternating ATO/chemotherapy strategy can be a post-remission treatment option in a subset of patients.