Purpose: The postoperative complication rate in mangled extremities is substantially high, irrespective of the nature of surgery performed. We attempted to identify the role of tissue vascular endothelial growth factor (VEGF) as a marker of neovascularization in skeletal muscle postinjury and its prognostic significance if any. Materials and methods: A pilot study, including 30 patients, was conducted at an advanced trauma center in PGIMER, Chandigarh in 2016. Patients were divided into 2 groups, based on the mangled extremity severity score, each containing 15 patients. Group I patients with a score of ≥7 were planned for amputation, whereas group II patients with a score of <7 were planned for limb salvage. Intra-op, skeletal muscle biopsies were taken in group I patients from three different zones. Zone A was the mangled zone; zone C was the clinically healthy zone, and zone B was the intermediate zone. Whereas, in group II, muscle samples were taken pre- and post-debridement. All the skeletal muscle samples were subjected to hematoxylin and eosin (H&E) stain followed by immunohistochemistry (IHC) examination with VEGF antibody in an attempt to identify viable muscle in various areas of the limb. Results: On H&E stained samples, in group I patients, the percentage of viable muscle fibers increases from 6.7 to 73% from zone A to zone C, whereas it increases from 7 to 80% in group II. On IHC stained samples, the median score was 0 (showed no positive staining) in all three zones of group I with a p value >0.05; whereas in group II, the median IHC score was 0 and 1 in pre- and post-debridement samples, respectively, with a p value of 0.004. Conclusion: The higher IHC scores in zone C in group I and post-debridement samples in group II, represent increased VEGF expression in these zones postinjury. This definite increase in VEGF expression, in turn, represents higher neovascularization activity in these zones as a response of the body to repair the damage postinjury.