Background: Although gut microbiota dysbiosis has recently been reported in HIV infected individuals, the relationship between the gut microbiota and immune activation in patients with different immune response to highly active antiretroviral therapy (HAART) is still not well understood. Gut microbiota and immune activation were studied in 36 non-HIV-infected subjects (Health Control) and 58 HIV-infected individuals which included 28 immunological responders (IR) and 30 immunological non-responders (INR) (≥500 and <200 CD4+ T-cell counts/µl after 2 years of HIV-1 viral suppression respectively) without comorbidities. Results: Metagenome sequencing revealed that the diversity and composition of gut microbiota could not be recovered completely as normal gut environment in HIV-infected individuals although with immunological response after long-term effective ART. At the genus level, predominant genera Fusobacterium, Ruminococcus_gnavus and Megamonas were more abundant, whereas Faecalibacterium, Alistipes, Bifidobacterium, Eubacteriumrectale, and Roseburia were depleted in IR and INR group than health control. Ruminococcaceae and Alistipes were positively correlated to nadir and current CD4+ T-cell, but negatively correlated to CD8+CD57+ T-cell. Inflammation markers and translocation biomarkers (LPS) levels were positively correlated to the abundance of genus Ruminococcus and Fusobacterium, but were negatively correlated to genus Faecalibacterium. Escherichia-Shigella and Blautia were enriched significantly in IR than INR group. Escherichia-Shigella were negatively correlated to CD4/CD8 ratio, but positively correlated to CD8+CD57+ T-cell. Conclusions: Altogether, the gut microbiota is one of the factors contributing to different immune response to HAART. Fusobacterium, Alistipes, Ruminococcaceae, Faecalibacterium and Escherichia-Shigella maybe the major genus contributed to different immune response in immunodiscordant and immunoconcordant patients on long-term suppressive ART.