Hemophagocytic lymphohistiocytosis (HLH) is a severe or even fatal inflammatory status caused by a hereditary or acquired immunoregulatory abnormality. Lymphoma-associated hemophagocytic lymphohistiocytosis (LAHS) is a kind of secondary HLH (sHLH). It suffers the worst outcome among sHLH. However, there is no standard treatment strategy. The argument mainly focuses on whether an HLH-directed or malignancy-directed approach should initially be adopted. Etoposide is one of the key drugs in HLH treatment and also shows activity in lymphomas. We sought to identify the importance of containing etoposide in the initial treatment of LAHS. 66 patients diagnosed with LAHS in our center during the three years were divided into two groups according to whether the initial treatment involved etoposide or lymphoma-directed chemotherapy without etoposide. The remission rate of the initial etoposide group (52 patients) is significantly better than that of the no initial etoposide group (14 patients) (73.1% vs. 42.9%, p = .033). The two-month survival rate (79.8% vs. 46.8%, p = .035) and overall survival (median survival time 25.8 w vs. 7.8 w, p = .048) of the initial etoposide contained group is significantly better. Multivariate cox analysis revealed that for patients without EBV infection (37 cases), initial treatment with etoposide could significantly improve prognosis (p = .010, Exp(B) = 0.183), but for patients with positive EBV, it shows a tendency. Containing etoposide is beneficial in the initial treatment of LAHS, whether in the HLH-directed or lymphoma-directed strategy. It provides higher response rate, lower mortality rate, and better survival, especially for EBV negative patients.