Background: The growth of acute myeloid leukemia (AML) cells not only depends on cell-intrinsic factors but is also supported by tumor microenvironment (TME), which can be reflected by Peripheral blood monocytes. This study was aimed to assess the role of peripheral blood monocytes as a marker for TME on the AML outcome exclusively in the non-M4/M5 subtypes to limit the confounding effect of the accompanying monocytosis. Patients and Methods: We prospectively analyzed the impact of absolute monocyte count (AMC) on the outcome of 44 adults with de novo non-M4/M5 AML. The AMC values were obtained at diagnosis by hematology automatic analyzer and patients were classified based on their AMC level generated by the ROC curve into two groups: low (≤0.4x10 9 /L) and high (>0.4x10 9 /L); including 16 (36.4%) and 28 (63.6%) patients, respectively. Results: The Median duration for followup was 8.2 (range 0.8-34.9) months, death, and relapse rates were significantly higher in the high AMC group, (P=0.028 and 0.001, respectively). There was no significant difference as regards complete remission, primary induction failure, or early death rates between both groups. Moreover, no statistical difference in 3-year Overall survival (OS) between low and high AMC groups except after ruling out early deaths (P=0.366 and 0.008, respectively). However, a statistically significant better Leukemia-Free Survival (LFS) was found in the low AMC group, (P=0.026). Conclusion: Peripheral blood monocytosis at the time of diagnosis, carries worse LFS and OS (only in patients without induction-related mortality) rates in non-M4/M5 AML patients.