Non-surgical therapy consisting of external beam radiation with or without chemotherapy is an effective treatment for patients with squamous cell carcinoma (SCC) of the oropharynx with advanced neck disease (N2a or greater). However, many of these patients have to undergo a neck dissection for clinically persistent regional disease. It is reported that nearly 50% of the neck dissection specimens contain residual viable tumor cells that may indicate partial radiation failure and as a consequence poor survival. In order to address the significance of this finding, we conducted a nonrandomized retrospective study, including 35 patients who underwent definitive radiation therapy followed by either a radical or modified radical (RND/MRND) or a selective neck dissection (SND) for clinically persistent neck disease 6 weeks after completing therapy for stage III/IV SCC of the oropharynx (base of the tongue =15, tonsil =12, soft palate =7 and pharyngeal wall =1). All neck dissection specimens were reviewed according to histological criteria indicating viable residual tumor. We observed an increased relative risk (RR) for local and regional failures in the patient population with viable cancer cells in the post-irradiation neck specimens (RR=6.7 and 4.1, respectively). The presence of malignant tumor cells in residual disease in the neck correlated with poor disease-specific and overall survival (P =0.03 and P =0.01, respectively). Of note, the extent of neck dissection did not improve the disease-free or overall survival in this patient population (P =0.5 and P =0.6, respectively). In conclusion, the presence of viable cancer cells in radiated neck nodes is a novel prognostic marker for disease-specific survival in patients treated for SCCs of the oropharynx with advanced neck disease and may serve as an identifier for patients who will benefit from post-treatment chemoprevention.