Objective To explore the efficacy and safety of doxycycline injection for macrocystic and mixed-cystic lymphatic malformations in children. Methods From September 2018 to December 2020, retrospective review of clinical data was performed for 13 children hospitalized with marcocystic and mixed-cystic lymphatic malformations receiving doxycycline injection. There were 6 boys and 7 girls with an average age of (3.9±3.6)(0.25-13) years. Preoperative ultrasound and magnetic resonance imaging (MRI) confirmed the diagnosis and classification. After general anesthesia, cyst was punctured, fluid drained and drug injected under ultrasound/laparoscopic guidance. Fluoroscopy was performed after injection to further evaluate the range of cysts and confirm that there was no drug overflow. During an initial follow-up period of 4-6 weeks after injection, physical and imaging examinations were performed. Based upon a comparison of preoperative and postoperative imaging data, the clinical responses were characterized as cure (volume reduction> 90% or surface invisible), effective (volume reduction> 50%), partially effective (volume reduction <50%) and no response. If the efficacy failed to reach the effective standard (no response or no change in appearance), protocol was repeated. Surgery was performed if re-injection remained ineffective. Results The lesions were located in head and neck (n=7), armpit (n=1), upper arm (n=1), chest wall (n=1), retroperitoneum (n=2) and popliteal fossa (n=1).One child had an operative history of head and neck. There was an average of 19(1.46±0.77) injections. The average follow-up period was (9±6.17)(4-27) months. The overall effective and cure rate was 100% and 69.2% respectively. Swelling, pain and vomiting after injection were relieved spontaneously or symptomatically. One case of hemorrhage in cyst improved after hospitalization for hemostasis. None of them had tetracycline tooth or nerve damage. Conclusion Doxycycline injection is effective for macrocystic and mixed-cystic lymphatic malformations with few adverse reactions. [ABSTRACT FROM AUTHOR]