BACKGROUND To compare the efficacy and safety of a homeopathic eye drop medicinal product (Homeoptic®) with 0.9% sodium hydrochloride eye drops (Larmabak®) in patients with mild-to-moderate dry eye disease (DED). METHODS Prospective, single-masked, observer-blinded, multicentre study on adult patients. Non-inferiority primary endpoint of the relative change between treatment groups in a composite Visual Analogue Scale (VAS) score covering five symptoms of DED, namely pain, itching, sensation of dry eye, impression of foreign body presence and burning, after 30 days of treatment. Details of all Adverse Events (AEs) were recorded and analysed. RESULTS Ninety three patients were randomised to each treatment arm. At Day 30, the mean VAS symptom score was 26.0 ± 18.8 in the Homeoptic® group and 32.8 ± 21.2 Larmabak® group. Homeoptic® was demonstrated to be non-inferior to Larmabak®: the mean treatment difference of -7 being below the 10 mm upper limit of the 95% CI ([-12.9; -1.0]) pre-set as significant. The superiority of Homeoptic® over Larmabak® was then established with detection of a significant difference between the two treatment groups (p = 0.022). Significant differences between the treatment groups in favour of Homeoptic® were also detected in isolated VAS scores for the symptoms dry eye sensation (p = 0.009) and burning (p = 0.004). Results of ocular surface staining tests to estimate corneal and conjunctival damage as well as patient satisfaction were also significantly in favour of Homeoptic®. No new safety concerns were identified. CONCLUSIONS Homeoptic® is more effective than Larmabak® at relieving the symptoms of DED and constitutes an effective treatment for mild-to-moderate DED.