AIM: To retrospectively investigate the association between dry eye symptoms and clinical or in vivo confocal microscopy parameters in patients with dry eye disease (DED), and to compare these parameters between eyes with DED and normal subjects. METHODS: This retrospective, cross-sectional, controlled study comprised 25 consecutive patients with non-Sjögren dry eye disease and age- and sex-matched 25 healthy subjects. Each patient underwent a complete examination of the ocular surface in the following order: tear osmolarity measurements, InflammaDry test, tear break-up time, corneal fluorescein staining, Schirmer I test, subjective symptoms questionnaire using the dry eye-related quality-of-life score (DEQS), and in vivo confocal microscopy analysis of the central cornea. Beck depression inventory (BDI) as depressive scale and history of medications and smoking were also evaluated. Stepwise multiple regression analysis was used to assess the factors affecting the DEQS. RESULTS: In univariate analysis, DEQS was associated with tear break-up time (ρ=-0.48, P=0.01), oral medications, such as hypotensive drug (ρ=0.56, P=0.004) and anti-depressant (ρ=0.57, P=0.003), and BDI (ρ=0.61, P=0.001) in patients with DED. In multiple regression analysis, explanatory variables relevant to the DEQS were the anti-depressant medications (P=0.04, partial regression coefficient B=21.04) and BDI (P=0.02, B=0.76, adjusted R2=0.54) in these patients. CONCLUSION: Our study shows a significant association between depression and dry eye symptoms. It suggests that dry eye symptoms associate with higher depressive symptoms and its medications, although our patients were not followed longitudinally.