Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Purpose: This study compares signs, symptoms and predictive tools used to diagnose dry eye disease (DED) and ocular surface disorders in six systemic well-defined and non-overlapping diseases. It is well known that these tests are problematic because of a lack of agreement between them in identifying these conditions. Accordingly, we provide here a comparative clinical profile analysis of these different diseases. Methods: A spontaneous and continuous sample of patients with Sjogren's syndrome (SS) (n = 27), graft-versus-host-disease (GVHD) (n = 28), Graves orbitopathy (n = 28), facial palsy (n = 8), diabetes mellitus without proliferative retinopathy (n = 14) and glaucoma who chronically received topical drugs preserved with benzalkonium chloride (n = 20) were enrolled. Evaluation consisted of a comprehensive protocol encompassing: (1) structured questionnaire - Ocular Surface Disease Index (OSDI); (2) tear osmolarity (TearLab Osmolarity System - Ocusense); (3) tear film break-up time (TBUT); (4) fluorescein and lissamine green staining; (5) Schirmer test and (6) severity grading. Results: One hundred and twenty five patients (aged 48.8 years-old +/- 14.1, male:female ratio = 0.4) were enrolled in the study, along with 24 age and gender matched controls. Higher scores on DED tests were obtained in Sjogren Syndrome (P<0.05), except for tear film osmolarity that was higher in diabetics (P<0.001) and fluorescein staining, that was higher in facial palsy (P<0.001). TFBUT and OSDI correlated better with other tests. The best combination of diagnostic tests for DED was OSDI, TBUT and Schirmer test (sensitivity 100%, specificity 95% and accuracy 99.3%). Conclusions: DED diagnostic test results present a broad range of variability among different conditions. Vital stainings and TBUT correlated best with one another whereas the best test combination to detect DED was: OSDI/TBUT/Schirmer.95Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundacao de Apoio ao Ensino, Pesquisa e AssistAancia do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo (FAEPA)NAP-FTO USPFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)