Objective: The significance of CTCs in patients with HNSCC is debated currently. We evaluated the potential detection of CTCs using the CellSearch (CS) Assay TM (Veridex, NJ, USA) in HNSCC patients and to identify the clinical factors predictive of the presence of CTCs in this population. Method: Forty-nine patients with locally advanced HNSCC were included. The presence and number of CTCs were determined using the CS system in all patients prior to the initiation of therapy, in 21 patients 3 months after treatment, and in 10 healthy individuals. Results: The CS system was able to detect the presence of CTCs in 8 of 49 patients (16 %) before therapy and in 4 of 21 disease-free patients (19 %) after therapy. No CTC was found in the control group. When considering the presence of CTCs before or after therapy, the presence of CTCs was statistically associated with patients' age (p=0.04; t-test) and N-stage (p=0.02; Fisher's exact test). Conclusion: CTCs are identified in a relatively low proportion of patients with locally advanced HNSCC and correlated with initial lymph node involvement. CTC detection could be a future useful prognostic tool to adapt the treatment intensity in HNSCC patients.