Abstract: OBJECTIVE To analyze the clinical features of immune reconstitution inflammatory syndrome (IRIS) in the patients with co-infection of human immunodeficiency virus (HIV) and Mycobacterium including Mycobacteria tuberculosis (MTB) or nontuberculous mycobacteria (NTM) after antiretroviral therapy (ART). METHODS A total of 51 patients with mycobacterial-IRIS who were treated in the Second Hospital of Nanjing from Jan. 2017 to Dec. 2024 were enrolled in the study. Among them, 32 cases were MTB-related IRIS (TB-IRIS), and 19 cases were NTM-related IRIS (NTM-IRIS). A retrospective analysis was performed on the demographic characteristics, clinical symptoms, and examination data of these 51 patients. The baseline data and clinical features were compared between the two groups. Additionally, the clinical laboratory test indexes were observed and compared between the two groups before the start of ART and at the confirmed diagnosis of IRIS. RESULTS The mortality rate was 0.00% (0/32) in the TB-IRIS group within 3 months after the conformed diagnosis, 5.26%(1/19) in the NTM-IRIS group, and there was no significant difference (χ²=0.071;P=0.790). At the time of confirmed diagnosis of IRIS, the incidence of lymph node involvement was 28.13% (9/32) in the TB-IRIS group, higher than 3.13% (1/32) in the NTM-IRIS group (P=0.047). The incidence of multiple lymphadenopathy was 50.00% (16/32) in the TB-IRIS group, 15.79% (3/19) in the NTM-IRIS group (P=0.015). The CD₄⁺T lymphocyte counts of the TB-IRIS group was significantly higher at the conformed diagnosis of IRIS than before ART initiation (P=0.002), while the HIV viral load was significantly lower at the conformed diagnosis of IRIS than before ART initiation (P=0.001). The hemoglobin level of the NTM-IRIS group was remarkably higher at the conformed diagnosis of IRIS diagnosis than before ART initiation (P=0.028), and the HIV viral load was lower at the conformed diagnosis of IRIS than before ART initiation (P=0.020). There were no significant differences in the levels of clinical laboratory test indexes between the TB-IRIS group and the NTM-IRIS group before the ART initiation. The CD₄⁺T lymphocyte level of the TB-IRIS group was higher than that of the NTM-IRIS group at the confirmed diagnosis of IRIS (P=0.043). CONCLUSIONS There is no specific test for diagnosis of co-infection of HIV and Mycobacteria-associated IRIS, and it may easily cause misdiagnosis. This study provides new ideas for clinical diagnosis and treatment of TB-IRIS and NTM-IRIS.