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Background and Objectives: Type 2 diabetes mellitus is usually associated with peripheral neuropathy, peripheral vascular disease with consequential limb ischemia, and eventually diabetic foot ulcers (DFUs). The healing process is slow due to microangiopathy and wound is easily infected with microbials leading to superficial infection, progressing to deep infection, and eventually landing in amputation most of the times. Platelet-rich plasma (PRP) is very cost effective, readily available blood derivative and has the capability to stimulate cell proliferation and differentiation. It improves tissue healing and regeneration and exhibit potent activities against a number of pathogens. Vacuum-assisted closure (VAC), on the other hand, is a new novel way to treat DFUs by having negative pressure wound healing. The present study focused on the advantage of (PRP + VAC) dressing over (topical PRP application with its peripheral injection) alone for aiding and enhancing the process of wound healing in DFU. Materials and Methods: This was a prospective comparative study of 100 cases to compare the outcomes of wound healing by topical PRP application with its peripheral injection. Results: Mean time taken for the appearance of granulation tissue, 100% granulation tissue, average reduction in wound surface area, showed significant (P ≥ 0.005) differences between the (PRP + VAC) and the (topical PRP application with its peripheral injection) dressing groups. Conclusions: (PRP + VAC) dressings are more effective than conventional (topical PRP application with its peripheral injection) dressings in wound healing of DFUs.