AIM: To evaluate the clinical efficacy of topical 0.05% cyclosporine nano-emulsion in the treatment of dry eye syndrome (DES) with meibomian gland dysfunction (MGD). METHODS: This prospective study included 64 patients with DES and MGD who were randomly assigned to three groups: Group 1 (n=24, conventional cyclosporine), Group 2 (n=21, nano-emulsion cyclosporine), and Group 3 (n=19, control). Lid margin telangiectasia (LMT), meibomian gland secretion (MGS), conjunctival injection (CI), corneal staining (CS), tear break-up time (TBUT), Schirmer test I (STI), Ocular Surface Disease Index (OSDI), and lipid layer thickness (LLT) was evaluated at 4, 8, and 12wk of treatment. RESULTS: In Group 3 (control), LMT, CS, and CI improved after 8wk, MGS, TBUT after 12wk of treatment. In Group 1 (conventional cyclosporine), LMT, MGS, and TBUT improved significantly after 4wk, whereas CS, CI, STI, and LLT improved significantly after 8wk, and OSDI at 12wk. In Group 2 (nano-cyclosporine), LMT, MGS, CS, CI, TBUT, and OSDI significantly improved after 4wk, and STI after 8wk. Especially, LLT was significantly higher than other groups after 4wk. CONCLUSION: Cyclosporine and nano-cyclosporine shows significant improvement in DES with MGD than the control group. In contrast, the nano-cyclosporine group shows more statistically improved CI and CS at 4wk, especially LLT at 4, 8, and 12wk compared to the conventional cyclosporine group.