Introduction: Bladder mucosa is anatomically covered by urothelial epithelium. The replacement of the urothelium with stratified squamous cells is defined as squamous metaplasia which can be keratinizing or non-keratinizing. Clinically, it is also known as leukoplakia or keratinizing cystitis of the bladder. Although several etiologic factors have been proposed such as chronic inflammation, irritative stimuli and infection, its pathogenesis is not clearly understood. The natural history of squamous metaplasia and clinical treatment are controversial. Many authors consider squamous metaplasia as a premalignant lesion, so it is fundamental to find an effective treatment to reduce the risk of developing bladder squamous carcinoma. Case description: We report our management of a 58-year-old man with histological evidence of keratinizing squamous metaplasia and severe lower urinary tract symptoms. After repeated transurethral resections, the patient was treated with intravesical instillation of hyaluronic acid showing the regression of the lesion with an improvement of macroscopic appearance followed by the resolution of clinical symptoms. Conclusion: The therapeutic management of keratinizing squamous metaplasia is controversial, and currently no effective medical therapy is available for its treatment. Actually, patients undergo transurethral resections and a multidisciplinary approach is required to avoid cystectomy. Annual cystoscopy with multiple biopsies should be performed to determine the presence of dysplasia. Moreover, the therapeutic treatment with hyaluronic acid instillations could be the starting point and the gold standard in the follow-up of our patient. However, at present, further studies are required to formulate an adequate policy for therapeutic management of this unusual lesion of the bladder mucosa.