Background: Pretreatment serum p53 and epidermal growth factor receptor (EGFR) were assessed using enzyme-linked immunosorbent assay (ELISA) in patients with acute leukemia to analysis their roles in characterization of different subtypes of the disease. Materials and Methods: Serum samples from thirty two patients with acute myeloid leukemia (AML) and fourteen patients with acute lymphoid leukemia (ALL) were analysed, along with 24 from healthy individuals used as a control group. Results: The results demonstrated a significant increase of serum p53 and EGFR in patients with AML (p<0.0001) compared to the control group. Also, the results showed a significant increase of both markers in patients with ALL (p<0.05, p<0.0001 respectively). Sensitivities and specificities for these variables were 52% and 100% for p53, and 73.9%, 95.8% for EGFR. Serum p53 and EGFR could successfully differentiate between M4 and other AML subtypes, while these variables failed to discriminate among ALL subtypes. A positive significant correlation was noted between p53 and EGFR. Negative significant correlations were observed between these variables and both of hemoglobin (Hg) content and RBC count. Conclusions: Mutant p53 and EGFR are helpful serological markers for diagnosis of patients with AML or ALL and can aid in characterization of disease. Moreover, these markers may reflect carcinogenesis mechanisms.