We have recently shown that topical application of sodium butyrate (SB) suppresses allergic contact dermatitis in mice. This effect was associated with the induction/activation of Treg, the activity of which is diminished in certain inflammatory dermatoses. To further study the effects of SB in chronic inflammatory skin disorders, we utilized the imiquimod (IMQ)-induced psoriasis-like skin inflammation model. Mice were treated with 5% IMQ cream (Aldara®) on the shaved backs and ears for 10 days. One group of IMQ-treated mice received topically on the back skin 100 µl of a 1 mM solution SB for 3 days. IMQ-treated mice developed thickening of the skin, erythema, scales as well as acanthosis, hyperkeratosis and inflammatory infiltrates. These inflammatory responses were significantly reduced upon administration of SB. On the RNA level, SB treatment leads to significant downregulation of Il17 transcription. In turn, transcription of Il10 was remarkably induced by SB. We surmise Treg to be the primary source of IL-10 which was supported by the upregulation of the mRNA of the Treg-specific transcription factor FOXP3. Together, these data support our assumption that SB might activate cutaneous Treg and thereby contribute to the downregulation of the inflammatory response. Though only topically applied, IMQ induces also systemic immunologic alterations. The number of IL-17-expressing CD45+ cells obtained from lymph nodes and spleens was remarkably enhanced in IMQ-treated mice, implying that the splenomegaly observed in IMQ treated mice may be in part due to the infiltration/expansion of IL-17+ lymphocytes. This effect was almost completely prevented by SB. In addition, significantly fewer CD45+ cells expressing FOXP3 and IL-10 were detected after IMQ administration, suggesting downregulation of Treg. Together, this implies that IMQ suppresses Treg and activates IL-17-expressing lymphocytes an effect which can be dramatically reversed by SB, explaining the beneficial effect of SB on the resolution of the IMQ-induced psoriasis-like lesions.