To consider the value of prognostic factors in the development of a squamous cell carcinoma from a leukoplakia of the oral mucosa, a retrospective study was performed. Clinical and histological data of 104 patients with oral leukoplakia were analyzed. Leukoplastic lesions with dysplasia in the initial biopsy (n = 38) had been treated by excision (n = 28), by laser evaporation (n = 6) or a combination of these treatments (n = 4). Non-dysplastic lesions (n = 66) had been excised (n = 48), evaporised (n = 17) or treated by excision as well as laser evaporation (n = 1). During follow-up of maximal 6 years (mean 3.6 years), 12 patients had developed an infiltrative squamous cell carcinoma at the site of the primary lesion, 2 within a period of 24 months. No relation could be found between on the one hand size (p > 0.2), clinical aspect (p > 0.2), location (p > 0.45), and primary treatment (p > 0.15) of the lesion, and on the other hand the risk of developing a squamous cell carcinoma. Only a relation could be found between (the intensity of) dysplasia and the development of a squamous cell carcinoma (p < 0.001). It was concluded that because of the high risk of developing a squamous cell carcinoma, patients with a dysplastic mucosal oral lesion should be followed during a prolonged time.