We sought to define the unfavorable group of core binding factor acute myeloid leukemia by analysis of c-KIT and FLT3-ITD (internal tandem duplication) and to correlate them with the treatment outcomes. The present study included 70 patients with core binding factor acute myeloid leukemia who had received “3 D 7” induction, followed by high-dose cytarabine consolidation. The presence of c-KIT mutations had no significant effects on overall or disease-free survival, but receptor tyrosine kinase mutations had negative effects on disease-free survival but not overall survival (P [ .04). Background: Core binding factor acute myeloid leukemia (CBF-AML) encodes 2 recurrent cytogenetic abnormalities, t(8;21) and inv(16), which carries an overall good prognosis. However, some patients will develop a relapse. We sought define the unfavorable group of CBF-AML by analysis of (c-KIT and FLT3-ITD) and to correlate them with treatment outcome. Patients and Methods: We performed a prospective study of 70 patients with CBF-AML diagnosed and managed at the medical oncology department of the (National Cancer Institute), Cairo University, with analysis of c- KIT and FLT3 mutations. All patients had received “3 þ 7” induction, followed by 3 to 4 courses of high-dose cytarabine consolidation. The institutional review board approved the present study. Results: The median patient age was 31 years (range, 18-60 years), with a male/female ratio of 4:3. Of the 70 patients, 42 (60%) had t(8;21) and 28 had inv(16) (40%). c-KIT mutations (exons 8 and 17) were detected in 10 of 52 tested patients, and FLT3-ITD was detected in 3 of 70 patients. Patients with inv(16) experienced more lymphadenopathy and splenomegaly, had a higher median initial leukocyte count. Hepatitis C antibody positivity (8 of 42) was exclusively present in patients with t(8;21). The median overall survival (OS) was 19.5 months, and the median disease-free survival (DFS) was not reached. Patients with inv(16) had near-significant (P ¼ .07) better DFS than patients with t(8;21). c-KIT mutations had no significant effect on OS or DFS. However, reverse tyrosine kinase mutations had a negative effect on DFS but not OS (P ¼ .04). Conclusion: CBF-AML with reverse tyrosine kinase mutation conveys a worse prognosis. Hepatitis C virus antibody positivity might be associated with t(8;21) AML and inv(16) with more extramedullary disease.