Neurofibromatosis (NF1) is an autosomal dominant tumour predisposition syndrome. A plethora of tumours are described in the literature associated with NF1. These tumours usually develop earlier in life. Some tumours show a close association with NF1, e.g. malignant peripheral nerve sheath tumour and optic nerve glioma, others are only rarely diagnosed in the context of this disease. This report focuses on the diagnosis and therapy of a squamous cell carcinoma (SCC) of the sole of the foot arising in a 67-year-old male patient with NF1. The lesion was initially misdiagnosed as an abscess. Wide excision of the highly differentiated SCC was followed by conditioning of the deep wound by a vacuum dressing. After achievement of bulky granulation tissue covering the defect at the level of the adjacent skin, a full-thickness skin graft was obtained from the abdominal skin and fixed on the defect. Healing of the defect was almost achieved by primary intention; two small lesions healed within weeks. The patient was repeatedly investigated. Five years after primary surgery, the patient had developed a corn on the medial side of the former defect. This lesion was completely excised and the defect was closed by primary intention after creating a small rotation flap. The lesion proved to be inflamed skin of the sole of the foot with no dedifferentiation of the epithelia. NF1 is a complex hereditary disease that displays an abundance of signs and symptoms. SCC may affect individuals with NF1. However, SCC account only for a small number of malignancies in NF1 compared to malignancies arising in connective tissue and brain. To the best of our knowledge, this is the first report on an SCC of the sole diagnosed in NF1. Vacuum dressing as an adjunct to surgery allowed reduced reconstructive measures.