Aim To analyze the impact of sex on GADD34 function, we studied the aging of female GADD34‐deficient mice and compared them with male GADD34‐deficient mice. Methods We used GADD34‐deficient mice on a C57BL/6 background. These mice were fed a normal diet throughout their life. Alternatively, they were fed a high‐fat diet at 3 months‐of‐age. Liver tissues taken from mice were analyzed by hematoxylin–eosin staining and immunohistochemical methods. Fresh liver cells were analyzed by flow cytometry. Results We found that female GADD34‐deficient mice did not develop obesity or fatty livers. However, female GADD34‐deficient mice had infiltrations of myeloid cells in the liver, followed by liver atrophy. Many female GADD34‐deficient mice developed hepatocellular carcinoma, whereas female wild‐type (WT) mice did not show hepatocellular carcinoma during aging. Female GADD34‐deficient mice and female WT mice developed the same percentages of lymphoma. Although a high‐fat diet induced a higher level of steatosis in young male GADD34‐deficient mice compared with WT mice, a high‐fat diet induced the same level of steatosis in young female GADD34‐deficient mice compared with WT mice. However, GADD34‐deficient female young mice had a higher level of infiltration of myeloid cells and myofibroblasts than WT mice. Conclusions In contrast to male GADD34‐deficient mice, female GADD34‐deficient mice did not show obesity as they aged. However, similar to the males, they developed inflammation followed by hepatocellular carcinoma. Geriatr Gerontol Int 2017; ••: ••–••.