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Background: Various rejuvenation surgeries, including hyaluronic acid (HA) fillers, aim to address mid-face volume loss. However, literature on the comparative efficacy and safety of different HA fillers for the zygomatic area remains limited. Methods: This systematic review and network meta-analysis (NMA), adhering to NMA PRISMA 2020 and Cochrane guidelines. Searches were conducted on different bases. Eligible studies included patients with mid-face volume loss undergoing HA interventions. The primary outcome was the Global Aesthetic Improvement Scale (GAIS) at different time points and the incidence of adverse events. Results: Among 1742 articles, six randomized controlled trials (RCTs) met the inclusion criteria with a total of 579 patients. The studies evaluated Giselleligne, VYC-20, Neuramis Lidocaine and ART-Filler. Results showed that Giselleligne demonstrated superior safety compared to VYC-20, ART-Filler and Neuramis-Lidocaine (Risk Ratios (RR) = 0.27, 95% Confidence interval (CI) [0.14; 0.54]), (RR = 0.36, 95% CI [0.17; 0.75], & RR = 0.22, 95% CI [0.07; 0.67]) respectively However, there were no significant differences in the Global Aesthetic Improvement Scale Assessment (GAIS) scores between HA fillers at 1, 3, and 6 months. Conclusion: While no significant differences were observed in efficacy among HA fillers, Giselleligne emerged as a potentially safer option for the cheeks volume restoration. The study emphasizes the need for further well-designed RCTs to explore the long-term safety and durability of HA fillers. These findings contribute valuable insights for clinicians and patients in making evidence-based decisions regarding mid-face rejuvenation options. [ABSTRACT FROM AUTHOR]