Objective：To investigate the clinical effect of 0.05% cyclosporine A and 0.1% tacrolimus eye drops in the treatment of severe dry eye associated with Sjögren’s syndrome. Methods：Fifty - six patients（112 eyes）with severe dry eye related to Sjögren’s syndrome，treated at the Department of Ophthalmology，Wuxi People’s Hospital Affiliated to Nanjing Medical University from October 2021 to November 2023，were enrolled. Patients were randomly divided into the tacrolimus group（n=28，56 eyes）and the cyclosporine A group（n=28，56 eyes）using a random control table. The tacrolimus group received 0.1% tacrolimus eye drops twice daily，while the cyclosporine A group received 0.05% cyclosporine A eye drops four times daily. Both groups underwent standard treatment for 8 weeks. Follow - up assessments included the Standard patient evaluation of eye dryness（SPEED），touch tear film break - up time （TBUT），Schirmer I test（SIt），corneal fluorescein staining（CFS）score before and after treatment. Results：There were no significant differences in baseline clinical data，pre -treatment SPEED scores，and TBUT between the two groups. Compared to pre -treatment， SPEED score and TBUT were improved in both groups after treatment. The tacrolimus group showed a more significant improvement in TBUT，whereas the Cyclosporine A group demonstrated a better improvement in SPEED scores. There were no significant differences between the two groups before treatment in CFS score and SIt index. Both groups showed improvement in CFS scores and SIt post - treatment，with similar improvement levels in CFS scores but a more significant improvement in SIt in the Cyclosporine A group. There were no significant differences in the morphology of meibomian gland and lipid layer thickness between the two groups before treatment. Post-treatment，both groups showed improvement in these parameters，with the tacrolimus group exhibiting more significant improvements. Some patients experienced transient irritation symptoms after using the two eye drops，and their irritation symptoms were relieved within 20 minutes after medication. Conclusion：Both 0.1% tacrolimus and 0.05% cyclosporine A have good therapeutic effects in severe dry eye associated with Sjögren’s syndrome，of which 0.05% cyclosporine A has more obvious advantages in improving patient comfort and reducing dry eye symptoms，while 0.1% tacrolimus has better effects in improving meibomian gland morphology and lipid layer thickness.