Hyaluronic acid (HA) and cyclosporine A (CsA) eyedrops are commonly prescribed in dry eye syndrome (DES). The effectiveness of each preparation in DES is well-known, yet the superiority of one over another has been studied little. We assessed the efficacy and tolerability of 0.15% HA compared to combinations of 0.05% CsA plus 0.5% carboxymethylcellulose (CMC), and 0.15% HA plus 0.05% CsA in patients with moderate to severe DES. Total 438 patients with moderate to severe DES were recruited and randomized for one of the three treatments for 12 weeks. Effectiveness was assessed at baseline, 4- and 12-weeks. The primary endpoint was change in corneal staining score. The secondary endpoints were tear break-up time (TBUT), strip meniscometry (SM) score, ocular surface disease index (OSDI) score, and tolerability questionnaire. The change in corneal staining score for 0.15% HA from the baseline was non-inferior to that of 0.05% CsA. Corneal staining score, TBUT, SM score, and OSDI score improved in all groups without statistically significant intergroup differences. Better tolerability and lower prevalence of adverse drug reactions were seen in 0.15% HA. Our findings suggest that 0.15% HA may be equivalently effective and safer than 0.05% CsA in treating moderate to severe DES.