Objective. The purpose of this prospective pilot study is to evaluate the effects of a novel perfusion-decellularized porcine hepatic-derived wound matrix (PDPHD-WM) on very difficult-to-heal diabetic foot ulcers (DFUs). Materials and Methods. For the intent of this study, a very difficult-to-heal DFU is one with a duration > 3 months despite using at least 1 advanced healing modality. Seven patients were enrolled in the study for a length of 14 weeks, including a 2-week run-in phase of standard-of-care therapy with saline gel and offloading in a CAM walker. Average wound duration was 25.5 months (range, 5–48 months). The PDPHD-WM was applied after the run-in phase and assessed weekly by the investigator. An average of 2.1 applications of the graft were performed (range, 1-4) over the study period. Results. Three patients (42.9%) reached complete wound closure, 2 had partial wound closure (28.6%), 1 (14.3%) had worsening of his wound, and 1 (14.3%) was removed from the study due to osteomyelitis. Average percent wound closure over the 12-week treatment period was 56% for all patients and 77% when only those wounds that improved were included in the data. In addition, a bimodal population distribution was noted in this small series. Patients who demonstrated an early response continued on to closure or near-closure (4 patients), while those who showed little or no early response remained unclosed at the end of the study. Conclusions. These results suggest that PDPHD-WM may be an appropriate modality to treat difficult-to-heal DFUs, and a larger randomized placebo-controlled trial should be performed to investigate these findings. To the best of the authors’ knowledge, this is the first collected data on using PDPHD-WM to treat DFUs.