Objective To explore the clinical characteristics and prognosis of secondary acute promyelocytic leukemia (APL) after therapy for hemophagocytic lymphohistiocytosis (HLH). Methods Clinical data of a child with Brevibacterium epidermidis infection-associated HLH and progressed to secondary APL following etoposide (VP16) therapy were collected, 17 cases reported in the literatures at home and abroad were reviewed. Results A case of Brevibacterium epidermidis infection-associated HLH treated in a hospital had secondary APL after receiving HLH-04 regimen, APL went into remission and patient survived after chemotherapy. 17 cases of secondary leukemia after therapy for HLH reported in literatures were reviewed, a total of 18 cases were included in analysis, 13 were males and 5 were females, the age of patients with the first diagnosis of HLH was 0-19 years (median 3 years), among the HLH types, EB virus infection-associated HLH accounted for 61%, the cumulative dose of VP16 was 400-20 500 mg/m² (median 3 100 mg/m²); the latent time of secondary leukemia was 6-72 months (median 26 months). Six of 18 cases died and 12 survived, 6 cases of M3 achieved complete remission and survived after chemotherapy. Conclusion Infection-associated HLH is a common type of primary disease in HLH-associated leukemia, APL has a high incidence among secondary leukemia. During therapy for HLH, it is necessary to pay attention to the cumulative dose, frequency of administration and combination regimen of VP16, as well as individual differences of patients, molecular biology of bone marrow is helpful to monitor the occurrence of secondary leukemia.