Summary Background Transforming growth factor (TGF)‐β1 exerts inhibitory effects on keratinocyte proliferation. Objectives To examine whether Smad7, a known inhibitor of TGF‐β1 signalling, is involved in psoriasis‐associated keratinocyte hyperproliferation. Methods Smad7 was evaluated in skin sections of patients with psoriasis and healthy controls and in mice with Aldara‐induced skin pathology by real‐time polymerase chain reaction and immunohistochemistry. To assess whether Smad7 positively regulates in vivo keratinocyte growth, mice treated with Aldara received daily cutaneous administration of Smad7 antisense oligonucleotide (AS). Keratin (K)6 and K16, cell‐cycle‐associated factors, cell‐cycle and cell proliferation were evaluated in HaCaT cells either treated with Smad7 AS or transfected with Smad7 plasmid and in mice given Smad7 AS. Results Smad7 was highly expressed in keratinocytes of patients with psoriasis and of mice treated with Aldara. In HaCaT cells, Smad7 knockdown inhibited cell growth, reduced K6 and K16 expression and promoted accumulation of cells in the S‐phase of the cell cycle. Smad7‐deficient keratinocytes exhibited reduced levels of CDC25A protein, a phosphatase that facilitates progression of cells through the S‐phase, and hyperphosphorylation of eukaryotic initiation factor 2 (eIF2)α, a negative regulator of CDC25 protein translation. Consistently, Smad7 overexpression in HaCaT cells was followed by induction of K6 and K16 and increased cell proliferation. Topical application of Smad7 AS to Aldara‐treated mice reduced epidermal thickness. Conclusions Our data show that Smad7 is overexpressed in human and murine psoriasis and suggest a key role of this molecule in the control of keratinocyte proliferation. What's already known about this topic? Defective transforming growth factor (TGF)‐β1/Smad signalling associates with the development of or exacerbates inflammation in many organs. Expression of TGF‐β1 and its receptors is reduced in psoriatic skin. What does this study add? Expression of Smad7, an inhibitor of TGF‐β1/Smad signalling, is upregulated in keratinocytes of patients with psoriasis and mice with psoriasis‐like skin inflammation. Smad7 knockdown with a specific antisense oligonucleotide (AS) induces keratinocytes to arrest in the S‐phase of the cell cycle, thereby reducing cell proliferation in both in vitro and in vivo models of psoriasis. What is the translational message? Our data show that Smad7 is a critical regulator of human and mouse keratinocyte proliferation. A Smad7‐specific AS reduces cell proliferation in both in vitro and in vivo models of psoriasis. The findings described in this work, together with our recent demonstration that Smad7 AS‐based therapy is safe and effective in patients with inflammatory bowel diseases, suggest that restoring TGF‐β signalling through Smad7 knockdown may help attenuate the pathological lesions in human psoriasis. Linked Comment: Gallucci. Br J Dermatol 2017; 177:1480–1481. Respond to this article