Background: Pharmacological management of acute leukemia remains a challenge. A seashell protein Haishengsu (HSS) has been found to exert anticancer activities in recent in vitro studies. The aim of this study was to determine whether the addition of HSS to the conventional chemotherapies would increase chemosensitivity and improves quality of life in patients with acute leukemia. Methods: Two hundred and forty-eight patients with acute leukemia were enrolled in a double-blind, and placebo-controlled study. In addition to conventional chemotherapy, 142 patients received HSS and 106 received placebo. In an in vitro study, the expression of P-gp was evaluated by flow cytometry in a drug-resistant leukemia cell line (K562/ADM cells). Sorcin was examined by Western blot. Results: The complete remission rates in the HSS treatment group were all higher than in the placebo group with non-relapsing leukemia and relapsed leukemia (p < 0.05). Less patients in the HSS group experienced gastrointestinal side effects from chemotherapy, whereas more patients had increased food take and an increase in Karnofsky performance status (KPS) score (p <0.01). In vitro, the expression of P-gp and sorcin in the HSS treated cells were lower than in the control group cells (p < 0.01). Conclusion: When added to conventional chemotherapy, HSS improves the complete remission rates and quality of life in patients with acute leukemia. The in vitro findings indicate that suppression of P-gp and sorcin genes in leukemia cells may be involved in the beneficial effects of HSS.