The transmembrane protein leucine-rich repeats and immunoglobulin-like domains 3 (LRIG3) regulates fat metabolism and bone morphogenetic protein (BMP) signaling. Lrig3-deficient mice exhibit impaired development of the snout and the inner ear lateral canal, neural defects, and cardiac hypertrophy in adulthood. However, no thorough and unbiased analysis of the physiological functions of Lrig3 has previously been performed. To address this knowledge gap, we performed histopathological examination of 42 tissues and organs from 1-year-old female C57BL/6JBomTac and 129S1-U mice with different Lrig3 genotypes. Among the scored pathologies, three were significantly associated with Lrig3 genotype: spontaneous macrovesicular hepatocellular degeneration (hepatocellular steatosis) was less prevalent in Lrig3-deficient C57BL/6JBomTac mice, whereas dilated or flaccid ileum and otitis media were more common in Lrig3-deficient 129S1-U mice. To further investigate hepatic steatosis phenotypes, 8-week-old C57BL/6JBomTac mice of both sexes and different Lrig3 genotypes were subjected to consuming a high-fat diet (HFD) for 8 weeks. The HFD regimen led to relatively few cases of hepatocellular steatosis, with no significant differences among the genotypes; however, female Lrig3-deficient mice presented reduced microvesicular hepatocellular degeneration compared with their wild-type littermates. This study revealed that Lrig3 regulates liver fat accumulation, intestinal morphology, and middle ear inflammation in a mouse strain-dependent manner.