Hyperkeratosis lenticularis perstans (HLP) or Flegel’s disease is a rare dermatosis characterized by asymptomatic hyperkeratotic papules predominantly located on the lower extremities. Lesional and non-lesional epidermis samples were studied by light- and electron-microscopic examination. The main ultrastructural finding was the presence of structurally altered Odland bodies/membrane-coating granules. Different therapeutic options for HLP have been reported, but none of the treatments was shown to be consistently effective. Here, we report on a patient with Flegel’s disease who did respond to topical 5-fluorouracil, whereas topical vitamin D3 synthetics were ineffective.