To assess and compare the therapeutic outcomes of 0.05% Cyclosporine A (CsA) ophthalmic solution versus 0.1% Fluorometholone (FML) eyedrops in Chinese patients with mild dry eye disease (DED) unresponsive to conventional artificial tears (AT).A total of 43 patients with mild DED, who have failed to respond to conventional AT therapy for over 3 months, were randomly assigned to receive either 0.05% CsA or 0.1% FML twice daily for 6-months. In addition, all the patients were instructed to use 0.1% SH 4 times a day as supplementary therapy. Dry eye examination, including Ocular Surface Disease Index (OSDI) questionnaire, non-invasive tear break-up time (NIBUT), Schirmer scores, corneal fluorescein staining (CFS) scores, and conjunctival goblet cell (CGC) density, intraocular pressure (IOP), Best corrected visual acuity (BCVA) was conducted at baseline and then evaluated at 1, 3, and 6 months after treatment. Corneal endothelial cell density, corneal dendritic cells (DCs) and nerves were assessed by in vivo confocal microscopy at baseline and 6 months after treatment.At 3 and 6 months after treatment, OSDI scores in the 0.05% CsA group showed more improvement than those in the 0.1% FML group. CFS was significantly lower and Schirmer scores were significantly higher in 0.05% CsA group compared with 0.1% FML group. NIBUT improved significantly in both groups, with greater improvement in the 0.05% CsA group at the 1-, 3-, and 6-month visits. Throughout the duration of the study, the 0.1% FML group exhibited no notable enhancement in CGC density. Conversely, a substantial elevation in CGC density was observed in the 0.05% CsA group. After 6 months of treatment, significantly reduced corneal DC density and area were obtained in 0.05% CsA group as compared to 0.1% FML group, while there were no significant changes in cornea nerve fiber density, cornea nerve fiber length and cornea nerve fiber width in both groups. Additionally, after 6 months of treatment, neither group showed any statistically significant changes in IOP, BCVA or in corneal endothelial cell density.The administration of 0.05% CsA proved effective in managing mild DED, offering a supplementary advantage in improving Schirmer scores, restoring CGC density and reducing corneal DC density compared to 0.1% FML eyedrops. Consequently, 0.05% CsA eyedrops are recommended as a safe and efficacious therapeutic alternative for patients with mild DED who fail to respond to conventional tear substitutes therapy.Chinese Clinical Trial Registry, ChiCTR2200066441, Registered 06 December 2022-Retrospectively registered.© 2024. The Author(s).