Endometrial cancer is an emerging disease with an increase in prevalence of aggressive histotypes in recent years. Background: In the present study, potential histopathological and immunohistochemical prognostic markers were investigated. Consecutive cases of high-grade non-endometrioid carcinoma (HG-NEC) of the endometrium were considered. Methods: Each surgical specimen was routinely processed; the most significant block was selected for immunohistochemistry and tested for ER, PR, ki67, p53, E-cadherin, β-catenin, Bcl-2 and cyclin D1. For each immunomarker, the percentage of positive tumor cells was evaluated (%) and dichotomized as low and high according to the distribution in the study population. Follow-up was collected for disease-free survival (DFS) and overall survival (OS). Thirty-three cases were eligible: 19 resulted in FIGO I–II; 14 resulted in FIGO III–IV. Twelve patients suffered a recurrent disease (mean follow-up 24.6 months); 8 patients died of the disease (mean follow-up 26.6 months). Results: Women with recurrent disease demonstrated a significantly higher Bcl2% (35.84 ± 30.96% vs. 8.09 ± 11.56%;p= 0.0032) while DOD patients had higher ki67% (75 ± 13.09% vs. 58.6 ± 19.97%;p= 0.033) and Bcl2% of border significance (34.37 ± 34.99% vs. 13 ± 17.97%;p= 0.078). As expected, FIGO III–IV had a worse DFS (HR = 3.34; 95% CI: 1.1–10.99;p= 0.034) and OS (HR = 5.19; 95% CI: 1.27–21.14;p= 0.0217). Bcl-2-high patients (Bcl2 > 10%) demonstrated a significantly worse DFS (HR = 9.11; 95% CI: 2.6–32.4;p= 0.0006) and OS (HR = 7.63; 95% CI: 1.7–34;p= 0.0084); moreover, PR low patients (PR ≤ 10%) had significantly worse DFS (HR = 3.74; 95% CI: 1.2–11.9;p= 0.02). Conclusions: HG-NEC represents a heterogeneous group of endometrial aggressive neoplasms with a worrisome prognosis, often at an advanced stage at presentation. Bcl-2 and PR may represent promising markers to identify a subgroup of patients having an even worse prognosis requiring a careful and close follow-up.