Second primary tumors in initially cured patients remain the greatest challenge in therapy for oral squamous cell carcinomas. The concept of field concerization is the most accepted hypothesis for the cellular and subcellular damages resulting in neoplastic transformation in the upper aerodigestive tract by risk factors such as chronic alcohol and tobacco abuse. Recent studies investigated several agents and regimens with benefit for chemoprevention of oral squamous cell carcinomas. In our review, the results of the most promising agents were studied. Despite discouraging results from recent intervention trials, studies in oral squamous cell carcinomas reported response rates up to 92%. In our investigation, two groups of patients were treated daily with 100 mg alpha-tocopherol, 75 mg beta-carotene, and 1000 mg ascorbic acid per os. The first group consisted of 24 patients with leukoplakia of the oral cavity. The second group included 24 patients with premalignant lesions after R0-resection of primary oral squamous cell carcinoma. Biopsies were taken from both groups prior to therapy and after 12 weeks follow-up. Flow cytometry analyses were performed and nucleolar organizing regions (NOR) were examined. An overall histological response rate of nearly 98% was noticed. Additionally, the pretherapeutic regimen increased cell kinetic parameters, such as the S-phase portion, and the average number of NOR per cell nucleus decreased. These results indicate that the chosen combination has substantial activity in oral premalignant lesions. Nevertheless, basic research is required in investigating valid biomarkers for chemoprevention studies.