Although the significance of immunohistochemical detection of DNA mismatch repair proteins and/or microsatellite instability testing in identifying patients at risk for germline deficiency in DNA mismatch repair genes is well established in colorectal carcinomas, the proper use of such techniques in sebaceous neoplasms, another tumor type that has been implicated in patients with hereditary DNA mismatch repair deficiency, has not been clearly defined. In this study, we stratified a series of 27 patients with 1 or more sebaceous neoplasms based on the pattern of immunohistochemical expression of MLH1, MSH2, MSH6, and PMS2, and comparatively analyzed their clinical and pathologic characteristics, including tumor-infiltrating lymphocytes and peritumoral lymphocytic response as determined by immunohistochemical staining for CD3. The study tissue samples included 30 sebaceous carcinomas, 14 sebaceous adenomas, and 7 sebaceous hyperplasias, along with 8 concurrent nonsebaceous lesions from 6 patients. Overall, 12 of the 27 (44%) patients showed abnormal IHC staining with mismatch repair proteins in their sebaceous tumors, the most commonly seen abnormality being concurrent loss of MSH2 and MSH6 (8/12, 67%). Sebaceous adenomas and carcinomas occurring in the same patients showed an identical staining pattern, as did hereditary nonpolyposis colorectal cancer-related nonsebaceous tumors in the same patients. When compared with cases that had normal expression of the mismatch repair proteins, cases with abnormal expression tended to be younger (median age, 56.5 y vs. 68 y), more likely to involve sites outside the head and neck (9/12 vs. 0/15), and more likely to have synchronous or metachronous visceral malignancies (8/12 vs. 3/15) and a positive family history. Furthermore, sebaceous tumors with abnormal expression had significantly higher CD3-positive tumor-infiltrating lymphocytes and peritumoral lymphocytic response. Thus, all these factors (age less than 60 y, involvement of nonhead and neck sites, visceral malignancy, family history fulfilling at least Bethesda guidelines, and lymphocytic infiltration) bore informative value in predicting abnormal expression of DNA mismatch repair proteins. However, their sensitivity was only modest, being 58%, 75%, 67%, 78%, and 75%, respectively. On such a premise, given that sebaceous neoplasms are only infrequently encountered, and that immunohistochemistry is easily available and reasonably reliable, we recommend that, when there exists a desire to identify hereditary DNA mismatch repair deficiency, routine immunohistochemical detection of DNA mismatch repair proteins be performed in all sebaceous neoplasms regardless of patient's age or other clinical characteristics.