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Purpose Since first being introduced over 50 years ago, ophthalmic viscoelastic devices (OVDs) have revolutionised the fields of cataract, cornea and glaucoma surgery, with extensive published anterior segment safety data available. More recently, these devices have also gained popularity in posterior segment surgery, with particular focus on their potential use as long-lasting, non-toxic, biocompatible and biodegradable vitreous substitutes. The most commercially available products are based on hydrophilic polymers such as hyaluronic acid (HA), hydroxypropylmethylcellulose (HPMC) and chondroitin sulfate (CS). This remains a novel area of research, with very few studies examining their long-term safety profile.Methods We conducted a systematic review on Medline and Embase via OVID, using key words “viscoelastics” and “intraocular”. Both databases were searched from inception date, with no language limitations.Results There is a paucity of high-quality evidence addressing the long-term safety of OVDs in the eye. A total of 38 studies were included for final review. These studies were unsuitable for any direct head-to-head comparisons; therefore, a descriptive analysis is presented.Conclusions By far, HA-based OVDs have been the most well described, with several long-term intraocular applications. They display highly favourable biophysical properties with minimal adverse reactions in short and long-term in vivo, in vitro and animal studies. There is limited safety data on HPMC and CS-based products, despite their popularity. This represents a gap in the literature and invites the need for high-quality evidence to support their continued use, particularly in the realms of vitreoretinal surgery and chronic hypotony.