The differential diagnosis of psoriasis affecting palmoplantar skin might be troublesome because of the anatomic properties of this region. Both palmoplantar psoriasis and eczematous dermatitis of this skin area share similar histologic features. The punch biopsies from 17 patients with psoriasis and 25 with eczematous dermatitis were evaluated, blind to the clinical diagnosis. Vertically situated multiple foci of parakeratosis, alternating with orthokeratosis, were the only statistically significant feature in the differential diagnosis of palmoplantar psoriasis [76.5% (13/17), p = 0.005]. In contrast, multiple foci of parakeratosis [70.6% (12/17)], loss of granular layer at least in focal areas [41.2% (7/17)], presence of neutrophils at the summits of parakeratosis [4% (1/17)], presence of neutrophils and/or plasma in the parakeratotoic foci [94.1% (16/17) and 11.8% (2/17)], psoriasiform epidermal hyperplasia [88.2% (15/17)], spongiosis restricted to the lower parts of the epidermis [47.1% (8/17)], dyskeratotic cells [82.4% (14/17)], thinning of suprapapillary plate [58.8% (10/17)], edema of the papillary dermis [29.4% (5/17)], presence of tortous and dilated capillaries in the papillary dermis [52.9% (9/17) and 76.5% (13/17)] and extravasated erythrocytes [29.4% (5/17)] were found to be more common in palmoplantar psoriasis compared with eczematous dermatitis; but none of them was statistically significant. Interestingly, spongiotic vesicles were seen in most of the patients with psoriasis [76.5% (13/17)]. In conclusion, according to our findings, many features of palmoplantar psoriasis overlapped with those of eczematous dermatitis. However, detection of multiple parakeratotic foci, placed vertically, alternating with orthohyperkeratosis, could be considered in favor of palmoplantar psoriasis.