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BACKGROUND As defensins are dysregulated in psoriasis, the present work is aimed at the assessment of the impact of topical betamethasone with and without calcipotriol on human beta-defensin 2 (hBD-2) expression and serum level in a cohort Egyptian psoriatic patients. METHODS A biopsy was performed at the site of psoriatic plaque for all patients participating in the study before application of any treatment. The first group of patients (n = 25) used an ointment containing a combination of calcipotriol and betamethasone dipropionate for 4 weeks while the second group (n = 25) used an ointment containing betamethasone valerate for the same period. For all patients, human beta defensin-2 expression and serum level was assayed before and after either treatment course. RESULTS No statistically significant difference way detected between both groups as regards PASI score, hBD-2 expression or serum level before application of either treatment regimen, while those who used the combined regimen showed lower expression and serum level of hBD-2 associated with lower PASI score on comparison with those who followed the mono-therapy. CONCLUSIONS Psoriasis treatment using the combined calcipotriol and betamethasone therapy is superior in effect to monotherapy using betamethasone alone. In addition, serum hBD-2 might be a useful marker for disease activity in psoriasis that can help assess the patient's clinical condition.