Large cyst-like periapical lesions can heal after nonsurgical root canal treatment. Decreasing the hydrostatic pressure within a periapical lesion can be achieved with the aspiration technique by using Endo Vac when there is drainage of cystic fluid through the canals. Clinical examination of a 21-year-old male patient revealed a large periapical lesion extending from the distal aspect of tooth #26 and reaching the mesial surface of tooth #22. During root canal treatment of teeth #23, #24, and #26, serous exudate drained from the root canal of tooth #24. The MacroCannula component of Endo Vac apical negative pressure irrigation system was used to aspirate the inflammatory fluid. The technique produces a vacuum effect in the periapical region through the root canal, which facilitates evacuation of large amounts of exudate. Two-year clinical and radiographic examinations revealed resolution of the mandibular radiolucency,. and the adjacent tooth #25 retained its vitality. The healing of a large periapical lesion can be achieved by the correct diagnosis and the proper treatment approach, without the need for surgery. EndoVac negative irrigation system might be useful for intracanal aspiration of exudates.