Background <p>Ewing sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents. Tumor-associated macrophages (TAMs) are a key component of the tumor microenvironment. While increased TAMs infiltration is linked to poor prognosis in various solid tumors, limited data are available regarding their role in sarcomas.</p> Methods <p>This retrospective study aimed to evaluate the frequency, density, and prognostic impact of TAMs in pediatric patients with ES treated at the Pediatric Oncology Department, National Cancer Institute (NCI), Cairo University. Immunohistochemical analysis of CD68 and CD163 expression was performed on 74 tumor tissue samples from pediatric patients with ES, which helps us understand the density of TAMs.</p> Results <p>The study cohort comprised 74 patients with a median age of 12 years (range: 0.5–18 years) and a male-to-female ratio of 0.8:1. The 5-year overall survival (OS) and event-free survival (EFS) rates were 48% and 42.8%, respectively. CD68 expression showed significant correlations with age at diagnosis (<i>p</i> = 0.035) and tumor size (<i>p</i> = 0.031) and near-significant associations with skeletal tumor location (<i>p</i> = 0.052) and complete response following induction chemotherapy (<i>p</i> = 0.054). CD163 expression was significantly associated with age at diagnosis (<i>p</i> = 0.046). However, neither CD68 (≤ 60 vs. &gt; 60) nor CD163 (≤ 90 vs. &gt; 90) levels showed significant correlation with survival outcomes (OS or EFS). Initial primary tumor site, tumor stage, post-induction chemotherapy disease status, and histological response to induction chemotherapy were significant predictor of survival outcome.</p> Conclusions <p>TAM markers (CD68 and CD163) did not demonstrate a significant prognostic impact on survival. Larger-scale studies are warranted to more precisely determine the role of TAMs in pediatric ES.</p>