BACKGROUND: Diabetes-related foot ulceration (DFU) represents a significant and increasing cause of morbidity and economic burden to health services. Surgical offloading has shown great effectiveness in the prevention and healing of DFU. The objective of this review is to assess the effectiveness of submetatarsal plantar fat pad modulation in preventing DFU and to characterise the different biomaterials used to this end. METHODS: The study was registered on PROSPERO. A search strategy of the PubMed, CINAHL and Cochrane biomedical databases was conducted. Any study which explored the modulation of the plantar submetatarsal fat pad for the prevention or treatment of DFU in adults was included. The main outcome was the occurrence of ulceration following intervention. RESULTS: Of the 3162 retrieved studies, 10 studies met inclusion criteria, describing outcomes for 76 participants with 112 ulcers or pre-ulcerative areas. Four studies report results of injectable liquid silicone in 55 participants, four studies included the use of an acellular allograft in eight participants, two studies included autolipotransplantation in 11 participants and one study reports on the use of injectable collagen in two participants. Only one randomised control trial was identified while the remainder of the studies were observational, case-series, or case-reports. The overall ulcer occurrence was 27/112 over an average follow-up of 32.4 months. DISCUSSION: While plantar fat pad modulation shows promise as a surgical offloading strategy for DFU, insufficient high-quality trial data preclude meaningful interpretation of its merits. This is further complicated by heterogeneity in the biomaterial employed for modulation.