Abstract Background: S100B protein was reported to be elevated in psoriatic patients' serum, with no previous evaluation of its skin expression, in contrast to the extensively studied S100 protein. Objective: To evaluate the serum level and skin expression of S100B in psoriasis to assess its possible involvement in its pathogenesis. Methods: Serum level of S100B protein was estimated in 40 psoriatic patients of different clinical varieties and 10 healthy controls. S100B protein expression was assessed immunohistochemically in lesional and non-lesional skin of patients and in normal skin of controls. Relation to disease severity was also evaluated. Results: Serum level of S100B protein was significantly higher in psoriatic patients (0.15±0.03 µg/l) than in controls (0.03±0.007 µg/l) (P-value <0.001) with no significant correlation with PASI score. On comparing grades of S100B protein skin expression in lesional and non-lesional skin biopsies, a statistically significant difference was found (P=0.046) with higher percentage of strong S100B skin expression (60%) in non-lesional than in lesional (42%) skin. All the control biopsies showed negative expression. Study limitations: Relatively small sample size with a limited range of low PASI scores. Conclusion: This study points to a potential link between psoriasis and S100B protein with higher serum and skin expression in patients than in controls.