Approximately 20% of human immunodeficiency virus (HIV)-infected patients do not achieve optimal CD4^＋ T cell recovery despite suppression of viral replication after antiretroviral (ART) treatment. These patients are referred to as immunological non-responders (INRs). However, the mechanisms involved are incompletely understood. This review summarizes the risk factors regarding the impaired immune reconstitution in HIV infection from the perspectives of clinical and immunological indicators. The speculated mechanisms of the failure of immune recovery may be the exhaustion of CD4^＋ T cells in peripheral circulation system, orchestration of cytokines and pyroptosis of CD4^＋ T cells at the gastrointestinal mucosal site. Specifically, microbial flora may contribute to the pyroptosis of CD4^＋ T cells at the intestinal mucosa-associated lymphoid tissue. Several clinical trials of additional treatment to ART that may improve immune reconstitution have been investigated but results thus far have proved disappointing because of the absence of medical evidence. Thus, prospective cohort study of larger samples should be conducted in future to define INRs, elucidate mechanisms and support clinical practice.