Summary Background LL‐37 is an antimicrobial peptide with pleiotropic effects on the immune system, angiogenesis and tissue remodelling. These are cardinal pathological events in systemic sclerosis (SSc). Objectives To elucidate the potential role of LL‐37 in SSc. Methods The expression of target molecules was evaluated by immunostaining and quantitative reverse‐transcription real‐time polymerase chain reaction in human and murine skin. The mechanisms regulating LL‐37 expression in endothelial cells were examined by gene silencing and chromatin immunoprecipitation. Serum LL‐37 levels were determined by enzyme‐linked immunosorbent assay. Results In SSc lesional skin, LL‐37 expression was increased in dermal fibroblasts, perivascular inflammatory cells, keratinocytes and, particularly, dermal small vessels. Expression positively correlated with interferon‐α expression, possibly reflecting LL‐37‐dependent induction of interferon‐α. In SSc animal models, bleomycin‐treated skin exhibited the expression pattern of CRAMP, a murine homologue of LL‐37, similar to that of LL‐37 in SSc lesional skin. Furthermore, Fli1+/− mice showed upregulated expression of CRAMP in dermal small vessels. Fli1 binding to the CAMP (LL‐37 gene) promoter and Fli1 deficiency‐dependent induction of LL‐37 were also confirmed in human dermal microvascular endothelial cells. In the analysis of sera, patients with SSc had serum LL‐37 levels significantly higher than in healthy controls. Furthermore, serum LL‐37 levels positively correlated with skin score and the activity of alveolitis and were significantly elevated in patients with digital ulcers compared with those without. Conclusions LL‐37 upregulation, induced by Fli1 deficiency at least in endothelial cells, potentially contributes to the development of skin sclerosis, interstitial lung disease and digital ulcers in SSc. What's already known about this topic? LL‐37, an antimicrobial peptide, has been shown to be upregulated in systemic sclerosis dermal fibroblasts. LL‐37 potentially contributes to dermal fibrosis through its antiapoptotic effect on those cells. What does this study add? LL‐37 potentially contributes to the development of skin sclerosis, interstitial lung disease and digital ulcers in systemic sclerosis. This further supports the critical role of antimicrobial peptides in the development of autoimmune and inflammatory diseases. What is the translational message? LL‐37 induction due to Fli1 deficiency in endothelial cells supports the notion that Fli1 deficiency is a key predisposing factor in the pathogenesis of systemic sclerosis. This has recently been demonstrated by the establishment of a new systemic sclerosis animal model, with mice double heterozygous for the Klf5 and Fli1 genes.