To establish criteria for differential diagnosis and to clarify the histogenesis of primary signet-ring cell carcinoma (SRCC) of the lung, five cases were studied by mucin-histochemical and immunohistochemical analyses and compared with SRCC of the gastrointestinal tract and mucus-producing adenocarcinoma of the lung. The proportion of signet-ring cell component varied from 10% to 90% in four cases, and the remaining tumor was a pure SRCC. Mucin-histochemistry showed a close similarity between lung SRCC and goblet cell-type or bronchial gland cell-type adenocarcinoma of the lung. Eighty percent of SRCCs showed positive immunoreactions for lactoferrin, a marker of bronchial gland cell differentiation, the results being consistent with the conclusions in previous studies that lung SRCC is closely related to bronchial gland cell-type adenocarcinoma. The incidence of K-ras mutation detected by the restriction fragment length polymorphism method was relatively high in lung SRCC (three of five) and goblet cell-type adenocarcinoma of the lung (four of four). Mucin-histochemistry indicated that lung SRCC has mucin production similar to that of the colon and colorectal-type SRCCs of the stomach but not to that of gastroduodenal-type SRCC of the stomach. Immunohistochemical staining for MUC-1 and MUC-2 glycoproteins showed a distinct difference; lung SRCC was positive for MUC-1 but negative for MUC-2, whereas colon SRCC and colorectal-type gastric SRCC were negative for MUC-1 but positive for MUC-2.Thus, by a combination of mucin-histochemistry and MUC-1 and MUC-2 immunohistochemistry, primary lung SRCC can be distinguished from metastatic lung SRCC originating in the gastrointestinal tract.