INTRODUCTION: The aim of this prospective randomized bicenter study was to compare the effects of continuous versus intermittent use of tear substitutes on the ocular surface and dry eye symptoms in patients receiving repeated and frequent intravitreal injections (IVIs) for neovascular age-related macular degeneration (nAMD). METHODS: Patients with nAMD treated with anti-vascular endothelial growth factor (anti-VEGF) for more than 1 year at 4-8-week intervals were included. The intermittent treatment group received standard 1.5% povidone artificial tears for three days after each IVI, while the continuous treatment group received an ophthalmic lubricant emulsion with 0.18% sodium hyaluronate four times a day throughout the study. The primary endpoint was the mean change in Ocular Surface Disease Index (OSDI) score between baseline and the day of the fourth IVI. Secondary endpoints included the Schirmer test score, tear break-up time (TBUT), and Oxford staining score. RESULTS: Sixty-five patients with mean age of 83.1 ± 6.0 years who had previously received a mean number of 28.5 ± 20.3 IVIs were included. The mean OSDI score change from baseline was -6.6 ± 13.5 points in the continuous treatment group versus +0.6 ± 13.7 points in the intermittent treatment group (p = 0.04). No significant differences in Schirmer test score, TBUT, and Oxford score were found between the groups. CONCLUSIONS: Continuous use of tear substitutes in patients with nAMD receiving repeated and frequent IVIs could be beneficial in improving dry eye symptoms, as shown by a significant improvement in OSDI scores in our study, despite no substantial changes in other ocular surface metrics. TRIAL REGISTRATION NUMBER: NCT06174181.