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 sjogren's syndrome. Methods: 112 eyes of 56 sjogren's syndrome patients with severe dry eye were continuously included between October 2021 and November 2023, all of them were divided into tacrolimus group (n=28, 56 eyes) and cyclosporine A group (n=28, 56 eyes) according to random comparison table method. The tacrolimus group received 0.1% tacrolimus eye drops twice a day, and the cyclosporine A group received 0.05% cyclosporine A eye drops four times a day. Both groups were treated for 8 weeks. Dry eye symptoms, tear film rupture time, tear secretion test and corneal fluorescein sodium staining score were followed up before and after treatment. Results: (1) There was no significant difference in general clinical data among all patients; (2) There was no significant difference in SPEED score and TBUT time between the two groups before treatment; Compared with before treatment, SPEED score and TBUT time were improved in both groups after treatment. Compared with each other, TBUT time in Tacrolimus group improved better, while SPEED score in cyclosporine A group improved better. (3) There were no significant differences between the two groups before treatment in FL score and SIt index; Compared with before treatment, FL score and SIt were improved in both groups after treatment. The improvement of FL score was similar between the two groups, but the improvement of SIt in cyclosporin A group was better. (4) There were no significant differences in the morphology of meibomian gland and lipid layer thickness between the two groups before treatment; Compared with the same group before treatment, the morphology and lipid layer thickness of meibomian gland were improved in both groups after treatment. Compared with each other, tacrolimus group had better improvement in meibomian gland morphology and lipid layer thickness. (5) Some patients experience transient irritation symptoms after using two eye drops, and their irritation symptoms are 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 Sjogren'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.