Hepatocyte transplantation holds great promise as an alternative approach to whole‐organ transplantation. Intraportal and intrasplenic cell infusions are primary hepatocyte transplantation delivery routes for this procedure. However, patients with severe liver diseases often have disrupted liver and spleen architectures, which introduce risks in the engraftment process. We previously demonstrated i.p. injection of hepatocytes as an alternative route of delivery that could benefit this subpopulation of patients, particularly if less invasive and low‐risk procedures are required; and we have established that lymph nodes may serve as extrahepatic sites for hepatocyte engraftment. However, whether other niches in the abdominal cavity support the survival and proliferation of the transplanted hepatocytes remains unclear.

Here, we showed that hepatocytes transplanted by i.p. injection engraft and generate ectopic liver tissues in fat‐associated lymphoid clusters (FALCs), which are adipose tissue–embedded, tertiary lymphoid structures localized throughout the peritoneal cavity. The FALC‐engrafted hepatocytes formed functional ectopic livers that rescued tyrosinemic mice from liver failure. Consistently, analyses of ectopic and native liver transcriptomes revealed a selective ectopic compensatory gene expression of hepatic function–controlling genes in ectopic livers, implying a regulated functional integration between the two livers. The lack of FALCs in the abdominal cavity of immunodeficient tyrosinemic mice hindered ectopic liver development, whereas the restoration of FALC formation through bone marrow transplantation restored ectopic liver development in these mice. Accordingly, induced abdominal inflammation increased FALC numbers, which improved hepatocyte engraftment and accelerated the recovery of tyrosinemic mice from liver failure.

Abdominal FALCs are essential extrahepatic sites for hepatocyte engraftment after i.p. transplantation and, as such, represent an easy‐to‐access and expandable niche for ectopic liver regeneration when adequate growth stimulus is present.