Background: Individualized treatment for patients with squamous cell carcinomas is most desirable. Biologic parameters of tumors may provide relevant criteria to achieve this goal. The aim of this study was: (1) to avoid elective neck dissection in patients with squamous cell carcinomas of the pharynx and supraglottis staged N0 by ultrasonography; (2) to administer postoperative radiotherapy only in patients staged ‘highly aggressive’ by biologic tumor parameters, in order to reduce patient morbidity and to improve quality of life. Study Design and Methods: This prospective trial was performed in 35 patients (any T stage, N0 or N1 by ultrasonographic examination). Tumor biopsies were taken for histological examination and for evaluation of some biological tumor markers. These parameters comprised DNA cytometric examinations, histological grading of the tumor front and immunohistochemical staining for proliferation markers (MIB1, PCNA). Based on these parameters, tumors were classified into ‘low aggressive’ (group 1) and highly aggressive (group 2) behavior. In all patients, second primaries were excluded by endoscopy, and the presenting tumor was resected with clear margins. In cases of ultrasonographically enlarged lymph nodes, functional neck dissection was performed. When biologic tumor profile showed low aggressive behavior (group 1), no postoperative radiotherapy was advised. In cases of highly aggressive tumors, radiotherapy was recommended postoperatively independent of all other parameters (group 2a and 2b). Results: The average follow-up was 36 months (range 16–65 months). Fifteen patients were included in group 1, 20 patients in group 2. Three patients with highly aggressive tumors who refused RTx were regarded independently (group 2b). In this pilot study of 35 patients, there was no difference in disease-free survival between group 1 and group 2a. Twenty-five of 35 patients were alive with no evidence of disease 29–65 months after treatment (3 died of disease; 5 died of second primary carcinomas; 2 died independent of disease). Eleven of 15 patients survived disease free in group 1, 13/17 in group 2a. In group 2b, 2 out of 3 patients, who were advised but refused postoperative radiotherapy, had recurrences. Conclusions: The results of this preliminary study point towards usefulness of some tumor biologic parameters in decision making for individualized treatment in patients with squamous cell carcinomas.