BACKGROUND: Peripheral lymphadenopathy can be caused by benign disease, or it could be a manifestation of underlying haematological disease or metastasis of a yet undiagnosed malignant condition. Fine-needle aspiration cytology (FNAC) and image- guided core biopsy usually make up the first line of investigation. There are several disadvantages to these techniques: FNAC is an acellular aspirate that may provide non- diagnostic specimens, while core biopsy may fail in the presence of composite lymphoma, nodal necrosis, and insufficiency or fragmentation of the specimens. Our aim was to evaluate the safety and effectiveness of excisional biopsy (EB) in a large case series. METHODS: 220 consecutive patients underwent lymph node EB under local anaesthesia. All patients underwent complete and systematic physical examination. Any palpable lymph node was evaluated for its location, size, consistency, fixation, and tenderness. All specimens were sent to the pathologist as fresh tissue. RESULTS: The EB materials demonstrated 89 (40.5%) benign lesions, 130 (59%) malignant diagnoses, and one (0.5%) unclear diagnosis. Mean operative time was 42.9 minutes (range 10-120 minutes). Harvested lymph nodes had a mean diameter of 3.3 x 2.3 cm. All patients were discharged within 8 hours. No major complications were reported, with a mean of 1.16 post-operative outpatient visits. Temporary seroma and/or minor lymph leak at the site of the incision occurred in 14 cases (6.4%), haematoma in 7 (3.2%), and dehiscence of the surgical incision in 4 (1.8%), and in 3 cases (1.4%) pain was reported up to 7 days post-operatively. CONCLUSIONS: Excisional biopsy is a diagnostic method that can be applied safely with minimal morbidity and mortality.