Pyoderma gangrenosum (PG) is an inflammatory skin disorder belonging to the group of neutrophilic dermatoses. Clinically, it is typified by cutaneous ulcers with distinctive erythemato-violaceous borders and may occur alone or in association with other inflammatory, autoinflammatory or neoplastic conditions. Although its pathophysiology remains incompletely understood, mounting evidence points towards a predisposing genetic background as well as a dysregulation of both the innate and adaptive immune responses, with follicular or epidermal structures as putative initial targets. To investigate genetic factors associated with PG susceptibility and severity (arbitrarily defined as unilesional and multilesional), whole exome sequencing was performed on eleven unrelated PG patients. Eight carried at least one variant in keratin encoding genes, including, KRT18, KRT20, KRT23, KRT32, and KRT33B. Strikingly, a recurrent variant (rs77999286) in the KRT18 gene was identified in 5/6 patients with multilesional and in 1/5 of those with unilesional PG. AlphaFold modelling and mutation analysis showed the destabilizing effect of the KRT18 rs77999286 variant on protein structure. Furthermore, immunohistochemistry revealed undetectable KRT18 staining in lesional as compared with healthy control skin. Overall, these findings suggest keratin variants may have a role in PG pathogenesis and indicate the KRT18 rs77999286 variant as a potential genetic factor linked to multilesional disease.