The purpose of the study was to compare the antitumor efficacy and safety profile of high-dose homoharringtonine as induction and post-induction therapy compared to either standard-dose homoharringtonine or daunorubicin in elderly patients with newly diagnosed acute myeloid leukemia. A total of 254 patients, age range 60-77 years received induction and post-induction therapy containing daunorubicin, standard-dose homoharringtonine, or high-dose homoharringtonine. After one course of induction therapy, the overall complete remission rate was similar between treatment arms (58.7%, P = .92). Among 161 patients with acute myeloid leukemia (non-M5 subtype), estimated median overall survival was 39, 29, and 37 months, respectively, in the daunorubicin, standard-dose homoharringtonine, and high-dose homoharringtonine treatment groups (P = .53). In the 93 patients with acute myeloid leukemia-M5 subtype, there was a significant difference in estimated median overall survival: 24, 24, and 52 months, respectively, in the daunorubicin, standard-dose homoharringtonine, and high-dose homoharringtonine treatment groups (P = .003). There was no significant difference in drug-related adverse events between treatment arms. High-dose homoharringtonine does not clearly increase the complete remission rate of elderly patients with acute myeloid leukemia. However, in the subset of elderly patients with acute monocytic leukemia, high-dose homoharringtonine as a first-line regimen prolonged overall survival with minimal toxicity.