Correct diagnosis of cervical lymphadenopathy is often a great challenge. The objective of this case study is to describe the distribution of the most common causes of unclear neck swellings presented in an ENT-Department and to evaluate the clinical history, examination and laboratory findings. In a retrospective study at the Department of Otorhinolaryngology, University Medical Center Homburg/Saar, 251 patients were enrolled with clinical and ultrasound signs of cervical lymphadenopathy as well as lymph node extirpation for histopathological evaluation. 127 patients (50.6 %) had a histological malignant finding. The distribution of the most common pathological conditions was as follows: Non-specific reactive hyperplasia n = 89 (35.5 %), metastases n = 86 (34.3 %), lymphoma n = 41 (16.3 %), granulomatous lesions n = 15 (6 %), abscess formations n = 5 (2 %), necrotic lymphadenitis and Castleman's disease one case of each, lymph node with normal architecture n = 7 (2.8 %), and neck masses mimicking lymphadenopathy n = 6 cases (2.4 %). The following factors identified by multivariate logistic regression were significantly associated to malignant lymphadenopathy: increasing age, generalized lymphadenopathy and history of malignant disorder, fixed neck masses and increasing diameter in ENT examination, bulky lesion, absence of hilus, blurred outer contour, protective role of the long form and decreasing Solbiati-index values by ultrasound B-Mode gray scale examination. Level II contained more benign lymphatic lesions, while the malignancy rate in level IV and V was enhanced. Laboratory parameters significantly associated to malignancies were CRP, LDH and thrombocytopenia. Patients with persisting cervical lymphadenopathy and over 3 weeks of antibiotic treatment should be considered for early biopsy, especially if some of the risk factors, pointed out in this study, are present.