To assess associations of dry eye disease (DED) severity of symptoms and signs with the quality of life in patients with moderate-to-severe DED. At baseline, 6 and 12 months, participants (N=535) were assessed for DED symptoms using Ocular Surface Disease Index (OSDI) and signs using conjunctival staining, corneal staining, tear breakup time (TBUT), Schirmer's testing, meibomian gland dysfunction, and tear osmolarity. Quality of life was evaluated using the Short Form Health Survey (SF-36), consisting of Physical Component Summary (PCS) and Mental Component Summary (MCS). Spearman correlation coefficients (rho) were used to evaluate correlations between the severity of DED and SF-36. At baseline, Worse DED symptoms indicated by higher OSDI total score were correlated with worse PCS (rho=-0.13, P=0.002) and MCS (rho=-0.09, P=0.03) of SF-36. The worse vision-related function was correlated with a worse PCS score (rho=-0.18, P<0.0001), and worse ocular symptoms were correlated with a worse MCS score (rho=-0.15, P<0.001). More severe DED signs including corneal staining (rho=-0.22, P<0.001), Schirmer test (rho=0.11, P=0.01), TBUT (rho=0.14, P<0.001), and tear osmolarity (rho=-0.12, P=0.02) were correlated with worse PCS score but were not correlated with MCS score (P≥0.39). ln longitudinal analysis, only worsening of ocular symptoms was significantly correlated with worsening of MCS score (rho=-0.09, P=0.04). In patients with moderate-to-severe DED, there were significant yet weak correlations between dry eye severity of symptoms/signs and physical or mental components of SF-36. Healthcare professionals should offer DED symptom relief and support for the emotional and practical challenges in their daily lives.