PurposeTo compare the effect of single-drop administration of two different ophthalmic solutions on tear meniscus and tear osmolarity in patients with mild to moderate dry eye disease. MethodsThis prospective study comprised of 122 patients with mild to moderate dry eye disease. These patients received a single dose of either unpreserved trehalose 3%, hyaluronic acid 0.15%, carbomer 0.25% (THHA, Thealoz Duo Gel) (Group 1) or hyaluronic acid 0.3% (HA) (Group 2) gel-based lubricants. Tear meniscus (height and depth) were measured using anterior segment optic coherence tomography (AS−OCT) at baseline and 10, 60, 120, and 240 min. after instillation. Tear osmolarity, Schirmer I test, tear break-up time (TBUT), gel properties, and patient comfort were evaluated 240 min. after instillation. ResultsTear meniscus height (TMH) and tear meniscus depth (TMD) showed a significant increase with both lubricants compared to the baseline (p < 0.001). This effect remained significant for up to 60 min. and 120 min. for the THHA and HA 0.3% solutions, respectively (p < 0.05, for both). Mean comfort duration was 115.1 ± 20.1 min. in Group 1 and 148.3 ± 49.0 min in Group 2 (p < 0.001). Tear osmolarity, Schirmer I test, and TBUT were similar between the baseline and 240 min. for each group. ConclusionsThe results of this study demonstrate that 0.3% HA remains on the ocular surface for longer than TH-HA. The longer ocular residency time also seems to correlate with a longer patient comfort duration.