AIM:To investigate the synergistic efficacy of travoprost and betahistine mesylate in early open angle glaucoma.METHODS:This study is a prospective, randomized, controlled, open label single center clinical trial that enrolled 82 patients(82 eyes)with early primary open-angle glaucoma from January 2020 to January 2023(eligible eyes were included, and the right eye was selected if both eyes met the inclusion criteria). The patients were randomly divided into a monotherapy group(41 eyes)treated with only travoprost eye drops and a combination therapy group(41 eyes)treated with travoprost eye drops and oral betahistine mesylate according to a 1:1 ratio using a random number table method. Followed-up for 12 mo, the intraocular pressure(IOP), retinal nerve fiber layer(RNFL)thickness, ocular hemodynamics [peak systolic velocity(PSV), end diastolic velocity(EDV), resistance index(RI), pulsatility index(PI)], liver and kidney function, quality of life, and clinical symptom scores before and after treatment were compared between the two groups of patients.RESULTS:Totally 4 patients were unable to complete all follow-up visits due to various factors, including 2 cases in the monotherapy group and 2 cases in the combination therapy group, with a lost rate of follow-up of 5%. The IOP in the combination therapy group was significantly lower than that in the monotherapy group at all time points(all P<0.05). Additionally, the rate of reduction in RNFL thickness was significantly slower in the combination therapy group compared to the monotherapy group(all P<0.05). Hemodynamic parameters revealed that PSV and EDV were significantly higher in the combination therapy group at 12 mo, while RI and PI were significantly lower than those in the monotherapy group(all P<0.05). The quality of life scores and visual analog scale(VAS)scores were also significantly better in the combination therapy group compared to the monotherapy group(all P<0.05). There were no statistically significant differences in liver functions, including alanine aminotransferase(ALT), aspartate aminotransferase(AST), total bilirubin(TBIL), and kidney functions, including serum creatinine(Scr), blood urea nitrogen(BUN), and uric acid(UA)between the two groups at 6 and 12 mo after treatment, with no serious damage to liver and kidney or other systemic adverse reactions observed in either groups. Furthermore, the incidence of headache in the combination group was lower than that of the monotherapy group(P=0.042), and there were no statistical significance in the incidence of other adverse reactions(all P>0.05).CONCLUSION:The combination therapy of travoprost and betahistine mesylate exhibits significant synergistic effects in patients with early primary open angle glaucoma, offering better IOP control, neuroprotection of the optic nerve, and oxidative stress inhibition. This combination may provide a new clinical reference for comprehensive glaucoma treatment.