Spontaneous apoptosis and expression of MCL1, BCL2, and BCL-XL may be useful prognostic markers in acute leukemia (AL) patients. The aim of this study is to examine the prognosis in adult leukemia patients based on spontaneous apoptosis and anti-apoptosis gene expressions in circulating leukocytes. In this study, newly diagnosed patients with acute myeloid leukemia (AML; n = 70) and acute lymphoblastic leukemia (ALL; n = 28) and 15 healthy controls were enrolled; apoptotic indices were calculated via flow cytometry using Annexin V/propidium iodide assay. The relative expression of anti-apoptotic genes was evaluated using real-time PCR. Early, late, and total apoptosis were significantly increased in peripheral blood leukocytes from patients diagnosed with AML and ALL compared to controls and in cases of ALL vs. AML (P < 0.001). Total apoptosis decreased significantly in AML and ALL patients who died early (ED; P = 0.001 and P = 0.002, respectively). Anti-apoptosis genes MCL1, BCL2, and BCL-XL were upregulated in 62.4%, 64.2%, and 62.4% of the AL patients, respectively. Among the AML patients, the upregulation of BCL2 was paradoxically associated with increased apoptosis and low rates of ED. The expression levels of MCL1 and BCL-XL had no significant prognostic values; among patients diagnosed with non-acute promyelocytic leukemia (APL)-AML, total apoptosis, expression of BCL2, and performance status were independent predictors of overall survival (OS). Overall, total apoptosis and BCL2 gene expression may be valuable independent markers for OS in patients with non-APL-AML in ALL patients. Moreover, decreased levels of spontaneous apoptosis were associated with ED, although this was not a significant predictor of OS.