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Purpose: The purpose of this study was to evaluate the diagnostic value of inter-eye osmolarity differences in relation to dry eye symptoms and other non-osmolar signs of dry eye disease. Patients and Methods: One hundred ninety one participants who attended a larger interventional study of dry eye disease prior to and after cataract surgery were analyzed for dry eye disease (DED). Dry eye diagnostics were performed for all subjects according to the DEWS II criteria: tear osmolarity was collected from both eyes with the TearLab system, non-invasive Tear film break up time (NIKBUT) was obtained on the test eye with Keratograph and ocular surface staining (OSS) was evaluated using the Oxford schema. The Ocular Surface Disease Index (OSDI) questionnaire was used to assess symptoms. Inter-eye osmolarity greater than 8, which is considered as a sign of DED according to the TearLab user manual, was evaluated and compared with other non-osmolar signs of DED. Results: The 191 subjects were divided into three groups according to osmolarity measurements. Sixty-five subjects had normal osmolarity (below 308 mOsmol/L in both eyes and less than 9 mOsmol/L difference between the eyes), 107 had high osmolarity (308 mOsmol/L or higher in one of the eyes) and 19 had an inter-eye difference > 8 mOsmol/L or higher, with neither eye having osmolarity higher than 307 mOsmol/L. Signs and symptoms in this last group were not correlated with the high osmolarity group or the normal group, though they appeared more similar to the normal group. Conclusion: The diagnostic value of inter-eye osmolarity difference in predicting symptoms or other non-osmolar signs of dry eyes appears weak. Our study suggests that the criterion of an inter-eye difference of 8 mOsmol/L is not a useful cut-off for diagnosing dry eyes based on osmolarity. [ABSTRACT FROM AUTHOR]