INTRODUCTION: The aim of the study was to systematically review the evidence from randomized controlled trials that evaluate the efficacy and safety of perfluorohexyloctane in the treatment of dry eye disease. METHODS: Literature search was conducted on PubMed and Scopus in April 2024 with the search strategy ("perfluorohexyloctane" or "NOV03" or "semifluorinated alkane") and "dry eye." Extension and paired-eyes study were excluded. The risk of bias was assessed using the Cochrane risk-of-bias tool. Forest plots and a summary of findings were prepared for total corneal fluorescein staining (tCFS), tear film break-up time (TFBUT), eye dryness score (EDS), and Ocular Surface Disease Index (OSDI). RESULTS: The pooled standardized mean difference (SMD) for tCFS after 8 weeks of treatment was -0.53 (95% CI: -0.68 to -0.38
p <
0.001), indicating a significant improvement in patients treated with perfluorohexyloctane. The between-study heterogeneity was moderately high (I2 = 52.0%). No significant differences in TFBUT were observed (SMD = 0.05
95% CI: -0.16 to 0.25
p = 0.654). Regarding symptoms, patients treated with NOV03 had significantly lower EDS compared to controls (SMD = -0.49
95% CI: -0.66 to -0.32
p <
0.001), with moderately high heterogeneity (I2 = 71.1%). Conversely, the pooled SMD of OSDI was -0.13 (95% CI: -0.43 to 0.17
p = 0.412), indicating no significant difference. CONCLUSION: Perfluorohexyloctane is an effective and safe alternative for the treatment of evaporative dry eye disease due to MGD that can significantly reduce tCFS and eye dryness symptoms. More well-designed non-sponsored randomized clinical trials are required to investigate the impact on other ocular surface parameters.