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 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 follow-up 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.