Objective To explore the clinical efficacy and influencing factors of omadacycline (OMC) in the treatment of patients with infectious diseases. Methods Data about hospitalized patients who received OMC monotherapy or combination therapy at Xiangya Hospital of Central South University from January 2022 to December 2023 were analyzed retrospectively. The influencing factors for failure of OMC treatment was analyzed by univariate and multivariate logistic regression analysis. Results A total of 160 patients were included in analysis, with an overall effective treatment rate of 69.4% (n=111). After treatment with OMC, patients in effective group was observed that body temperature improved (［36.83±0.52］℃ vs ［37.85±0.92］℃, P<0.001), white blood cell count (［7.78±4.07］×10⁹/L vs ［10.06±6.49］×10⁹/L, P<0.001), procalcitonin (［0.63±1.19］ ng/mL vs ［4.43±10.14］ ng/mL, P=0.001), C-reactive protein (［35.16±37.82］ mg/L vs ［105.08±99.47］ mg/L, P<0.001), and aspartate aminotransferase (［50.50 ±40.04］ U/L vs ［77.17±91.43］ U/L, P=0.004) all decreased significantly. Only one patient had adverse reactions such as diarrhea, but treatment was not interrupted. Univariate ana-lysis showed that patients in failure treatment group had a higher acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score (17.0 ［9.5-22.0］ vs 12.0 ［9.0-19.0］, P=0.046) and sequential organ failure assessment (SOFA) score (7.0 ［4.5-10.0］ vs 4.0 ［2.0-9.0］, P=0.019). Multivariate analysis showed that end-stage liver disease (OR=77.691, 95%CI: 5.448-1 107.880, P=0.001), mechanical ventilation (OR=6.686, 95%CI: 1.628-27.452, P=0.008) and the combination treatment of vancomycin (OR＝6.432, 95%CI: 1.891-21.874, P＝0.003) were risk factors for the failure of OMC treatment, while the course of OMC treatment (OR=0.905, 95%CI: 0.825-0.994, P=0.037) was a protective factor for the effective treatment. Conclusion OMC can be used as an alternative therapy for refractory severe infection, with fewer adverse reaction. End-stage liver disease, mechanical ventilation and combination treatment of vancomycin are risk factors for failure of OMC treatment in infected patients. Adequate OMC treatment course can improve patients’ clinical outcome, large-scale case studies are needed to confirm the initial conclusion.