Background & Objectives: Accurate differentiation of eczema and psoriasis can be difficult, especially in areas of palm and sole. This study was designed to evaluate histopathological features and identify statistically significant parameters in distinguishing palmoplantar psoriasis from eczema of these regions in patients referring to Razi Skin Hospital, Tehran, Iran. Methods: In a cross-sectional study, the patients referring to Razi Skin Hospital were subjected. Biopsies of 36 patients with palmoplantar psoriasis and 16 patients with eczema of these regions were collected from archive of pathology. All of the biopsies were examined blind to the clinical diagnosis by four dermatopathologists separately and data collection forms were completed. Then obtained data were analyzed by SPSS software. Results: The females were more affected than males. There was no difference on involving palm and sole between psoriasis and eczema. Hypogranulosis (P<0.0001), Monro’s microabscess (P<0.0001), tortuous blood vessels in papillary dermis (P<0.0001), suprapapillary plate thinning (P=0.020), confluent parakeratosis (P=0.044) and spongiform pustule (P=0.047) were found to be statistically significant contributors to the clinicopathological concordance in cases of psoriasis. Plasma mounds (P=0.022) were significantly associated with diagnosis of eczema. Conclusion: Psoriasis was more common than eczema in the palms. Histopathologic finding like hypogranulosis, Monro’s microabscess, tortuous blood vessels in papillary dermis, suprapapillary plate thinning, confluent parakeratosis and spongiform pustule had significant relationship with psoriasis and might be useful for its diagnosis.