Background: To evaluate the clinical efficiency of the treatment of dry eye disease (DED) with ocular pain using deproteinized calf blood extract (DCBE) eye drops as compared to 0.3% sodium hyaluronate (SH) eye drops. Methods: This prospective, single-center, masked (double-blind), randomized controlled study included 53 patients divided into two groups: DCBE (n=22) and SH (n=31) group. The DCBE group received DCBE eye drops for 4 weeks, and the SH group received 0.3% SH eye drops for 4 weeks. Corneal fluorescein staining (CFS) scores, tear break up time (TBUT), Schirmer test and the ocular surface disease index (OSDI) scores were evaluated in all patients before treatment, 2 and 4 weeks post-treatment. Results: The DCBE group showed better improvement in the OSDI light sensitivity scores and ocular pain scores compared with the SH group (P<0.05). At 2 and 4 weeks post-treatment, the DCBE group and the SH group showed significant improvement in TBUT, Schirmer test, CFS, OSDI score, light sensitivity score and ocular pain score (P<0.05) compared with the data from before treatment. Conclusions: This study indicates that DCBE eye drops can relieve ocular pain and light sensitivity in dry eye patients better than SH eye drops.