We performed a single-center, prospective trial to investigate the efficacy of PEG- asparaginase combined with liposomal doxorubicin, etoposide, and methylprednisolone (L-DEP) as an initial therapy for Epstein-Barr virus driven hemophagocytic lymphohistiocytosis (EBV-HLH). None of the patients received any chemotherapy after the diagnosis of EBV-HLH between September 2019 and September 2021. The efficacy was evaluated 2 weeks and 4 weeks after initiating L-DEP primary therapy. Forty-seven eligible patients with EBV-HLH were enrolled. The overall response rate (ORR) was 80.9% (38/47, 12 in clinical CR, 26 in clinical PR) at 2 weeks after the L-DEP regimen; at 4 weeks, the ORR was 75.6% (34/45, 21 in clinical CR, 13 in clinical PR). EBV-DNA loads in blood and plasma were significantly decreased 2 and 4 weeks after the L-DEP regimen (P < 0.001). Ferritin, soluble CD25 (sCD25), triglycerides (TGs), and ultrasonic spleen longitude, and thickness were all decreased significantly 2 and 4 weeks after the L-DEP regimen (P < 0.001). Thus, the L-DEP regimen is an effective initial therapy for EBV-HLH. However, the L-DEP regimen was poor in terms of long-term prognosis and that allo-HSCT should be received as soon as possible once a complete response is achieved.