Opportunistic infections often occur in immunocompetent hosts. Human immunodeficiency virus (HIV) infection and underlying diseases that can cause immunodeficiency or immune disorders are the main susceptibility factors. In recent years, it has been found that there are some new potential immunodeficiency mechanisms such as anti-cytokine antibody diseases and primary immunodeficiency diseases that are closely related to various opportunistic infections such as Talaromyces marneffei, non- Tuberculous mycobacteria and Aspergillus infections in non-HIV hosts. Moreover, many problems including clinical infection phenotype, immunodeficiency regulation mechanisms and treatment strategies have drawn increasing attention. This review summarized the potential mechanisms of immunodeficiency and opportunistic infections in non-HIV hosts.