Cyst-like periapical lesions should be treated initially with conservative nonsurgical procedures. In this case series, we describe the clinical and radiographic outcomes of large cyst-like lesions that were treated by orthograde decompression and long-term intracanal use of calcium hydroxide [Ca(OH)2] mixed with 2% chlorhexidine digluconate. Ten cases of cyst-like periapical lesions involving 15 teeth from 10 patients were selected. Maximal radiographic diameters of the lesions ranged from 11 to 28 mm. Nonsurgical procedures were performed, including apical patency, orthograde puncture of cyst-like exudates, chemomechanical preparation, and placement of intracanal Ca(OH)2/CHX dressings, which were periodically replaced during 6–10 months. The root canals were then filled with gutta-percha and sealer. The follow-up periods ranged from 6 to 24 months, and the outcome was classified as healed, healing, or failure. Nine lesions drained copious exudates after canal patency. One lesion only drained bloody serous exudate after periapical overinstrumentation. In 9 patients, intracanal exudation ceased in the first follow-up visit. At the 24-month follow-up, 6 lesions (60.0%) had healed, and 3 lesions (30.0%) were healing, with the corresponding patients being without clinical signs or symptoms. The case of treatment failure was submitted to surgical treatment. Microscopically, the lesion appeared to be an apical cyst with exuberant extraradicular bacterial biofilms attached to the sectioned root apex. This case series supports the use of nonsurgical methods to resolve larger cyst-like periapical lesions.