Background Fanconi anemia (FA) is characterized by congenital anomalies, progressive bone marrow failure, and increased cancer risk. FA patients have a >300-fold increased risk of developing head and neck cancers, including oral squamous cell carcinoma (OSCC). Objective To describe the spectrum of premalignant/malignant oral lesions illustrating diagnostic and management challenges in patients with FA. Methods Five patients with FA seen regularly were selected. Oral lesions and management strategies were systematically documented over time. Results All 5 patients with FA (4 male; 1 female; median age 21) developed oral lesions without evidence of human papilloma virus or typical risk factors for OSCC. All patients had received previous hematopoietic cell transplantation. Three patients developed OSCC of the lateral tongue (n = 2) and gingiva (n = 1), preceded by rapidly progressing premalignant epithelial dysplasia. All 3 had previous history of graft-vs-host disease, a known risk factor in patients with FA. Patients with OSCC developed recurrent/new dysplastic lesions within 4 years following management of OSCC. The 2 patients with no OSCC showed premalignant epithelial dysplasia and verrucous hyperkeratosis of the tongue and palatal gingiva, respectively. One patient with OSCC also developed pharyngeal wall SCC and 2 separate basal cell carcinomas of the upper lip. Our current management strategies include frequent evaluation (monthly to every 3-6 months) with low tolerance and recommendation for biopsy of suspicious lesions. Conclusions Patients with FA develop premalignant lesions and OSCC at a younger age and higher rate than non-FA patients and require screening examinations for such lesions at least every 6 months. Lower biopsy thresholds and histologic evaluation are recommended. Fanconi anemia (FA) is characterized by congenital anomalies, progressive bone marrow failure, and increased cancer risk. FA patients have a >300-fold increased risk of developing head and neck cancers, including oral squamous cell carcinoma (OSCC). To describe the spectrum of premalignant/malignant oral lesions illustrating diagnostic and management challenges in patients with FA. Five patients with FA seen regularly were selected. Oral lesions and management strategies were systematically documented over time. All 5 patients with FA (4 male; 1 female; median age 21) developed oral lesions without evidence of human papilloma virus or typical risk factors for OSCC. All patients had received previous hematopoietic cell transplantation. Three patients developed OSCC of the lateral tongue (n = 2) and gingiva (n = 1), preceded by rapidly progressing premalignant epithelial dysplasia. All 3 had previous history of graft-vs-host disease, a known risk factor in patients with FA. Patients with OSCC developed recurrent/new dysplastic lesions within 4 years following management of OSCC. The 2 patients with no OSCC showed premalignant epithelial dysplasia and verrucous hyperkeratosis of the tongue and palatal gingiva, respectively. One patient with OSCC also developed pharyngeal wall SCC and 2 separate basal cell carcinomas of the upper lip. Our current management strategies include frequent evaluation (monthly to every 3-6 months) with low tolerance and recommendation for biopsy of suspicious lesions. Patients with FA develop premalignant lesions and OSCC at a younger age and higher rate than non-FA patients and require screening examinations for such lesions at least every 6 months. Lower biopsy thresholds and histologic evaluation are recommended.