BACKGROUND: Creeping fat is a characteristic of Crohn's disease and impacts the disease course. We evaluated creeping fat formation, focusing on innate lymphoid cell-mediated fibrogenesis and its clinical significance. METHODS: Patients with inflammatory lesions in the ileum (the most commonly affected area), who underwent surgical resection at Osaka University or Hyogo Medical University (n = 34), were included. The ileum and mesentery were obtained from three sites: the control, non-creeping fat part, and creeping fat part. The distribution and properties of the innate lymphoid cells were analyzed by cell isolation. Furthermore, the correlation between macrophages and their effects on adipose tissue and clinical course were also investigated in a prospective cohort study. RESULTS: Group 1 innate lymphoid cells in creeping fat were increased, correlating with inflammatory macrophages in the mesentery and showing higher interferon-gamma expression. Co-culture experiment involving stromal vascular fraction from the control mesentery and Group 1 innate lymphoid cells from creeping fat revealed increased mRNA expression of fibrosis-related genes and inflammatory markers of macrophages, although these changes were nullified by interferon-gamma-neutralizing antibody. Next, we examined the clinical importance of Group 1 innate lymphoid cells and identified their high frequency in creeping fat as a risk factor for early recurrence (P = 0.008, odds ratio: 1.19). Furthermore, the higher Group 1 innate lymphoid cell frequency group (>/= 80%) had shorter relapse-free survival (P = 0.03). CONCLUSIONS: Group 1 innate lymphoid cells and inflammatory macrophages contribute to creeping fat formation via interferon-gamma secretion, affecting post-surgery intestinal outcomes.