Marjolin's ulcer is described as malignant lesions developed in the injured skin, which can cause several kinds of malignancies. Our results showed that no HER2 but p53 was detected in Majorlin's ulcer samples. Meanwhile, by statistical analysis, we found that the positive rate of p53 in Majorlin's ulcer samples was associated with the pathological type of ulcer canceration and degree of tumor differentiation. The positive expression rate of vascular endothelial growth factor (VEGF) was 62.5% in poorly differentiated squamous cell carcinoma (SCC), 39.4% in moderately differentiated SCC, and 66.7% in well-differentiated SCC, respectively. Furthermore, some cases of Majorlin's ulcer with positive P53 were negative for VEGF, while some cases with positive VEGF were negative for P53. Image superposition showed that VEGF expression was absent or minimal in p53-positive cases. However, P53 was not expressed or rarely expressed in VEGF-positive cases. Our results of this study will suggest that P53 can be used as the mark of Marjolin's ulcer differentiation, and there may be some interaction between P53 and VEGF in Marjolin's ulcer. The regulation of microenvironment in the oncogenesis, progression, and differentiation of Marjolin's ulcer is complex and needs further study.