Abstract Background: Chronic non-healing ulcers represent a significant burden to patients and healthcare systems, particularly in diabetic and trophic ulcers. Conventional dressings often require frequent changes and prolonged hospital stay. Autologous Platelet-Rich Fibrin Matrix (PRFM) has emerged as a regenerative modality promoting wound healing through sustained release of growth factors. Aim: To compare the efficacy of autologous PRFM dressing with conventional povidone-iodine dressing in the management of diabetic and trophic ulcers. Materials and Methods: This prospective comparative study was conducted over 18 months (2022–2024) in a tertiary care hospital. A total of 100 patients with chronic ulcers were randomly allocated into two groups: Group A (Cases): PRFM dressing (n=50) Group B (Controls): Conventional povidone-iodine dressing (n=50) Patients were assessed for reduction in wound surface area, wound depth, duration of hospital stay, and total number of dressings required. Statistical analysis was performed using Student’s t-test and Mann-Whitney U test. Results: The mean percentage reduction in wound surface area was significantly higher in the PRFM group (64.2 ± 8.52%) compared to controls (49.7 ± 7.83%) (p<0.001). Mean wound depth reduction was also superior in the PRFM group (79.3 ± 10.1%) versus controls (60.4 ± 12.0%) (p<0.001). The PRFM group had significantly shorter hospital stay (10.5 ± 3.2 days vs 20.4 ± 6.19 days) and required fewer dressings (6.32 ± 1.22 vs 25.0 ± 3.86). Conclusion: Autologous PRFM dressing is a safe, effective, and superior alternative to conventional dressings in chronic diabetic and trophic ulcers, offering faster healing, reduced hospital stay, and improved patient compliance.