Background: Based on clinical and histomorphological study, differentiating Chronic Plaque Psoriasis from chronic eczematous lesions of palmoplantar region is a diagnostic challenge, however, it has some implications for the patient's management and prognosis. Aim: This study is designed to evaluate immunohistochemical markers for distinguishing psoriasis from eczema of palmoplantar region in patients referring to Razi Skin Hospital, Tehran, Iran. Materials and Methods: Comparative cross-sectional study was carried out at Razi Skin Hospital, Tehran, Iran. Immunohistochemical stains for VEGF, Ki67, and GLUT-1 were performed on 45 cases including 15 patients with palmoplantar psoriasis, 15 patients with palmoplantar eczematous lesions, and 15 patients with diagnosis of lichen planus as control group. Results: The expression of Ki-67 were not significantly different between psoriatic and eczematic lesions but it was more severe in patients with psoriasis. VEGF staining showed a higher vascular proliferation in psoriasis than in eczema and lichen planus. There was no significant difference between GLUT1 expression in 3 examined groups but most cases of psoriasis show diffuse distribution for GLUT1 staining compared with eczema and lichen planus, which mostly show discontinuous staining for GLUT1 marker. Conclusion: Our findings indicate that VEGF immunostaining shows a significantly more expressed vascular proliferation in patient with psoriatic lesions, and can be helpful as immune marker for differentiating palmoplantar psoriasis and eczema of this region.