Objective To explore the clinical efficacy and safety of oxymetazoline hydrochloride in the treatment of rosacea-related persistent facial erythema.Methods A total of 87 patients with rosacea-related persistent facial erythema received in our hospital from June 2020 to March 2021 were selected as the research objects, and they were divided into the experimental group and the control group by computer random number method, of which 43 cases were in the control group single external application of 0.1% tacrolimus ointment treatment, 44 cases in the test group were treated with oxymetazoline hydrochloride on the basis of the control group. The efficacy index scores, clinical efficacy, skin function indicators, and incidence of adverse reactions were compared between the two groups of patients after 2 months of treatment.Results The difference of curative effect index scores between the two groups before and after treatment was higher in the experimental group than in the control group (P < 0.05); the clinical effect of the test group was better than that of the control group (P < 0.05); the difference of erythema and transdermal water shunt loss before and after treatment in the experimental group was higher than that in the control group (P < 0.05); there was no significant difference in the incidence of adverse reactions between the two groups (P < 0.05).Conclusion Oxymetazoline hydrochloride in the treatment of patients with rosacea-related persistent facial erythema can help to further reduce the amount of facial erythema and improve the patient's facial erythema symptoms. The clinical effect is good and does not significantly increase the adverse drug reactions.