[Introduction] Liver is a center of carbohydrate and lipid metabolism and deeply involved with the development of metabolic syndrome. If a method to comprehensively capture the biological and pathological changes in the liver caused by obesity could be established, it would contribute to the development of drugs or functional food ingredients to prevent lifestyle-related diseases. In this study, we performed SWATH-mass spectrometry of livers obtained from high-fat diet (HD)-induced obese mice. [Methods] Six weeks old C57/BL/6J male mice were fed with HD, or normal diet (ND) for 5 weeks. On the day 35, livers were collected after 16 h of fasting. Proteins extracted from the liver tissues were digested by trypsin, and the resulting peptides were analyzed by a nanoLC-MS/MS (SCIEX, TripleTOF5600+ system). Ion library of liver protein digests was built by data dependent analyses （DDA） and database search were performed against Uniprot mouse protein database. The SWATH measurements were performed under three conditions in which the amount of protein (3 ug or 5 ug), the Q1 window width (25 Da or variable) and number (25 or 50), and the MS/MS accumulation time (50 or 100 msec) were changed. [Results and Discussion] In total, 1,524 proteins were successfully quantified. Among them, 121 and 107 proteins increased by more than 1.2 times in the HD and ND, respectively (p <0.05). Compared to the ND, the amount of many proteins involved in detoxification and respiratory chain decreased in the HD group, some of which were consistent with previous reports, while the amount of proteins involved in cell-autonomous immunity, lipid metabolism, and Fe metabolism increased in the HD group. This results suggested the possibility that high-fat diet intake and increased serum cholesterol may be linked through abnormalities in iron metabolism.