Purpose To compare the efficacy and safety of an artificial tear combining the polymers carboxymethylcellulose (CMC) and hyaluronic acid (HA), to a formulation of CMC alone in subjects with dry eye. Methods A preservative-free artificial tear (CMC-HA) was compared with an existing artificial tear (CMC). Subjects with mild-to-severe signs and symptoms of dry eye were enrolled in this double-masked, randomized, multicenter trial, and dosed at least twice daily for 90 days, with follow-up visits at Days 7, 30, 60, and 90. Ocular Surface Disease Index (OSDI) was the primary outcome measure. Secondary outcome measures were tear break-up time (TBUT), ocular surface staining, Schirmer test with anesthesia, and visual analog scale (VAS) scores of dry eye symptom severity and formulation acceptability. Safety measures included adverse events, biomicroscopy, and visual acuity. Results A total of 460 subjects were enrolled across 45 sites (38 in Europe; 7 in Australia), of whom 454 were randomized to receive treatment. The per-protocol (PP) population consisted of 394 subjects, 364 (92.4%) of whom completed the study. In the PP population, the mean ± SD change from baseline in OSDI score at the primary timepoint, Day 90, was −16.9±17.5 for CMC-HA and −16.0±16.1 for CMC. CMC-HA was non-inferior to CMC based upon a confidence interval method. Both treatments significantly improved ( P <0.001) OSDI, symptom VAS scores, TBUT, and ocular surface staining from baseline at all follow-up visits, with minimal differences between groups. Greater reduction of overall ocular pain/discomfort was reported in subjects using CMC-HA versus CMC ( P =0.048). Approximately 10% of subjects in each group reported treatment-related adverse events of generally mild to moderate severity. Conclusion The new CMC-HA formulation was effective and well tolerated, and demonstrates a greater potential for symptom relief compared with CMC. These data support implementation of this formula for the management of dry eye patients.