Objective: To observe the clinical effects of systemic administration assisted with intratympanic injection of glucocorticoid combined with hyperbaric oxygen on sudden deafness (SD) and its influences on inflammation and stress response of the patients. Methods: From June 2015 to November 2018, 128 patients with SD at the Otolaryngology Department of the Fourth People’s Hospital of Langfang City were included in this study, all patients were randomly divided into group A (n=64) and group B (n=64). Group A was treated with systemic glucocorticoid administration combined with hyperbaric oxygen, and group B was treated with glucocorticoid tympanic injection on the basis of group A. After treatment, the mean pure tone threshold, curative effect, plasma C-reactive protein (CRP), nitric oxide (NO) level and nitric oxide synthesis rate-limiting enzyme nitric oxide synthase (NOS) activity were compared between the two groups. The adverse reactions and complications were recorded in the two groups. Results: 1) Compared with those before treatment, the mean pure tone auditory threshold decreased significantly after treatment in both groups (P<0.05), but the decreasing amplitude and auditory threshold gain in group B were higher than that in group A (P<0.05); 2) there were no statistically significant differences between the two groups in overall efficiency and significant efficiency of SD below moderate level (P>0.05), but the overall efficiency and significant efficiency of SD above severe level in group B were higher than those in group A (P<0.05); 3) there were no statistical differences in CRP and NO levels and NOS activity before treatment between the two groups (P>0.05). CRP level decreased, NO level and NOS activity increased after treatment between the two groups (P<0.05), but the change degree of group B was greater than those of group A (P<0.05); 4) no serious adverse reactions and complications occurred in both groups. Conclusion: Intratympanic injection assisted with systemic administration of glucocorticoid combined with hyperbaric oxygen can yield better results in SD above severe level, which may be attributed to reduced inflammation and stress response.