BACKGROUND: Lhermitte-Duclos disease (LDD) is a hamartomatous overgrowth of cerebellar ganglion cells, which replace granular cells and Purkinje cells. In recent years several cases involving the association between LDD and Cowden's syndrome (CS), an autosomal dominant condition characterized by multiple hamartomas and neoplastic lesions in skin and internal organs, have been reported. METHODS: We reviewed the medical records and imaging studies of six patients with LDD who were treated at our institution, and we looked at other possible symptoms of CS. RESULTS: Other clinical findings suggestive of CS were apparent in five patients: These included mucocutaneous lesions, acral keratosis, thyroid adenoma, fibrocystic disease, ovarian cyst, intestinal polyposis, and arteriovenous malformation. Only in the youngest patient, a 5-year-old boy, were no cutaneous or other signs found, despite extensive clinical and ultrasound examination. CONCLUSION: Our observations strengthen the hypothesis that LDD is a neurological manifestation of CS. Patients with LDD should receive a thorough dermatological and systemic screening, because some of the lesions (breast, etc...) can develop into malignant tumors.