Malignant tumors presented in hernia sac are very rare and the clinicopathological features are not well studied. We retrospectively reviewed 21 patients with cancers identified in surgically resected hernia sac specimens at our institution, including 14 males and 7 females, with a median age of 65 years (range 35–93). Fourteen patients (66.7%) carried a synchronous or metachronous cancer diagnosis elsewhere and the tumors in hernia sac were proven to be metastasis. Of the remaining seven (33.3%) cases, hernia sac tumors were the initial presentation of malignancy, and a panel of immunohistochemistry markers were applied in combination with clinical information to identify tumor origin. The final classification of all 21 cases was as follows: 11 gastrointestinal tract tumors including 10 adenocarcinomas and 1 gastrointestinal stromal tumor, 5 pancreatobiliary adenocarcinomas and 5 gynecological serous carcinomas. Compared to other tumor types, pancreatobiliary adenocarcinomas were more likely to involve hernia sac as initial presentation before a primary site was identified (P = 0.0307) and had worse survival (P < 0.005). As the first and largest cohort of malignant tumors in hernia sac, our study provides critical data on frequency, distribution, clinicopathological features and applicability of immunohistochemical markers to determine tumor origin in cases with unknown primary.