In this study, we evaluated the expression of SHP-1 (PTPN6) in endometrioid (Ec) and serous (Sc) subtypes of endometrial carcinoma by immunohistochemical analysis. In total, 114 patients with Ec carcinoma and 48 patients with Sc carcinoma were enrolled in this study. The correlation between the type of histology, the grade of tumor, the stage of development, and immunoreactivity to SHP-1 was evaluated. Kaplan-Meier and multivariate survival analyses, using a Cox regression model, were performed to establish whether this marker has prognostic value in these malignancies, on the basis of follow-up and stratification of the patients according to their SHP-1 immunoreactivity. A significantly higher SHP-1 expression was observed in the Ec group compared with the Sc group (P=0.0005, Fisher exact test). In the Ec group, SHP-1 immunoreactivity was correlated with grading, demonstrating that more differentiated lesions expressed SHP-1 more frequently than less differentiated neoplasms (G1 vs. G2, P=0.0243, statistically significant value, Fisher exact test; G1 vs. G3, P=0.0088, extremely significant value, Fisher exact test). Instead, in the Sc group, SHP-1 expression was not correlated with grading, as Sc is now defined as a high-grade carcinoma. SHP-1 expression did not change with neoplastic progression in Ec and Sc groups. From both univariate and multivariate analysis in the Ec group, expression of SHP-1 remained a positive prognostic factor (P=0.004, log-rank test) [HR=0.32 (0.11 to 0.94), P=0.039]. In contrast, in the Sc group, no correlation between SHP-1 expression and survival was noted (P=0.77, log-rank test). In this study, we observed that the absence of SHP-1 in immunohistochemical analysis might serve as a marker of poor prognosis for a subset of high-grade endometrial cancer.