Endometrial cancer (EC) is the most common malignancy of the female reproductive system in the industrialized world. Similar to other common diseases, gene variations are believed to be able to alter an individual's predisposition to developing the disease. The CHEK2 gene encodes a tumor suppressor that takes part in various cell processes, including cell cycle regulation, DNA repair, and apoptosis. The polymorphic variant Ile157Thr in exon 3 of the gene has been demonstrated to enhance the risk of several types of cancer and at the same time to reduce the risk for developing other cancer types. To study the significance of CHEK2 I157T for EC, we have genotyped 268 patients and 449 female controls. We found carriers of I157T more often among controls than we did among patients (2.45% vs. 1.75%), but the difference was not statistically significant. Case-only analysis revealed that the variant is overrepresented in patients diagnosed at 75 or more years of age (9.09%, p = 0.05) and in those with deep myometrial invasion (3.85%, p = 0.06). The highest frequency was observed in patients with both the aforementioned characteristics (20%, p = 0.01). Tumors of I157T carriers showed endometrioid, clear cell, and mucinous morphology, which suggested that the variant may not be restricted to a certain histotype of the disease and could even be overrepresented in rare ones. This study is the first to explore the association between germline CHEK2 I157T and EC. It suggests the need for further large-scale evaluation of the role this variant plays in endometrial carcinogenesis.