Imiquimod 5% is approved for topical treatment of actinic keratosis (AKs), superficial basal cell carcinoma and condylomata acuminata, the 3.75% formulation for the treatment of AKs and genital warts. Imiquimod has also been used off‐label in various other skin conditions (eg, Bowen's disease, lentigo maligna, vulvar intraepithelial neoplasia). As a toll‐like receptor 7/8 (TLR7/8) agonist imiquimod induces a local inflammatory response by increased production of cytokines, co‐stimulatory molecules, activation of Nk‐cells and antigen‐specific T‐cells. In addition to imiquimod‐associated adverse effects at non‐application sites such as fever, vertigo or myalgia there have been anecdotal reports of distant inflammatory mucosal reactions—a side effect not declared in the medicinal product information. In this scoping review we collected a total of seven cases of patients with lesions of the oral mucosa and lips and summarized pathophysiological hypotheses to explain this type of side effect. The review is complemented with an illustrated report of a 87‐year‐old female patient of ours suffering from chronic lymphocytic leukemia (CLL) who developed severe oral mucosal and labial reactions following application of imiquimod 3.75% for treatment of AKs. She denied accidental transfer of imiquimod and was tested negative for herpes simplex virus (PCR) and bacteria (culture) from lesional swabs.