Isolated syphilitic cervical lymphadenopathy (SCL) is a rare presentation of syphilis. Two patients with isolated SCL are presented here with a review of the literature. The first patient was a 72-year-old man with a mass (diameter 5 cm) in the right neck region for 26 days. Serological tests, imaging studies and pathological examination of the mass after surgical excision confirmed the diagnosis of isolated SCL. The second patient was a 48-year-old man with a mass (diameter 4 cm) in the right neck region for 1 month. The diagnosis of isolated SCL was made on the basis of serological tests, cervical ultrasound and pathological examination of the mass after surgical excision. Complete excision resulted in a satisfactory outcome in both patients. Isolated neck masses without associated clinical manifestations or adverse personal history are a diagnostic challenge, and SCL is easily overlooked in the differential diagnosis. Unusual masses should always remind clinicians of this infectious disease and a comprehensive diagnostic strategy is recommended. Nonroutine syphilitic serological tests should be performed in patients suspected of having SCL, and the histopathological and immunohistochemical characteristics may help to confirm the diagnosis.