Purpose: To compare the effect of topical application of tacrolimus 0.03% eyedrops versus cyclosporine 0.05% in Sjogren syndrome subjects with severe dry eyes. Design: A prospective single-blinded simply randomized controlled study. Methodology: 60 Sjogren patients were randomized into Group A: 30 patients were instructed to put tacrolimus 0.03% eyedrops in one eye for 6 months and placebo eyedrops in the other eye, ( N = 30, 44.9 ± 12.58 years). Group B: 30 patients were instructed to put cyclosporine 0.05% eyedrops in one eye for 6 months and placebo eyedrops in the other eye ( N = 30, 49.4 ± 12.92 years). Main outcome measures: Patients were evaluated at day 0, 90, and 180 for Ocular Surface Disease Index Questionnaire (OSDI), frequency of use of artificial tears, average fluorescein tear break up time (TBUT), ocular surface staining scores, Schirmer I test, meibum quality, and expressibility scores. Results: Upon comparing both eyedrops, the mean value of OSDI decrease was 38.25 ± 18.29% versus 31.69 ± 18.57% ( p-value 0.09), SICCA score decrease was 2.97 ± 1.92 versus 2.27 ± 2.02 ( p-value 0.124) the decrease in artificial tear substitute use was 3.90 ± 2.22 versus 3.63 ± 1.92 ( p-value 0.616), increase in Schirmer I values were 4.10 ± 4.21 and 4.26 ± 2.00 ( p-value 0.590) in eyes treated with tacrolimus and cyclosporine respectively. Neither of them affected meibum quality or expressibility scores. Conclusion: Both tacrolimus and cyclosporine significantly improved patient symptoms, frequency of artificial tears use and ocular surface staining compared to placebo-controlled eyes. However, no significant difference regarding the efficacy of both eyedrops at the end of 6 months treatment of severe dry eyes of Sjögren syndrome patients. Trial registration: ClinicalTrials.gov. Identifier: NCT03865888.