The combination of calcipotriol (Cp) and topical corticosteroids increases efficacy and reduces side effects as compared to monotherapies. Previous studies suggest that such combinations may have an added value with respect to reduction of T-cell subsets. A two-compound product consisting of Cp and betamethasone dipropionate (BD) has become available for the treatment of psoriasis and is clinically superior to both monotherapies. No immunohistochemical data are available on the in vivo effects of the two-compound formulation versus monotherapy with respect to the three key processes in psoriasis pathogenesis: epidermal proliferation, epidermal differentiation and inflammation. Therefore, 18 patients were treated with the two-compound product, Cp monotherapy or BD monotherapy for 6 weeks and biopsies were taken before and after 4 and 6 weeks of treatment. These biopsies were stained immunohistochemically and analysed (semi)quantitatively. All treatments decreased the number of Ki-67(+) cells and increased the keratin 15(+) staining. A more pronounced reduction of epidermal and dermal T-cell markers and human beta defensin-2 was seen following combination treatment, compared with both monotherapies. In conclusion, the investigated markers of the skin immune system and epidermal proliferation indicated an added value of the two-compound product over both monotherapies.