Discriminating between patients with microbial infections that cause secondary immune effects from those with the same infection who have primary immune deficiency disease can be difficult. There are many microbes that temporarily “stun” innate and/or adaptive immunity during a primary infection. The common result of temporary inhibition, or permanent depletion of host immunity during some primary infections is the development of superinfections of other microbes that cause significant morbidity, and on occasion, mortality. In addition, microbes that cause persistent infection, such as the human immune deficiency virus, deplete effective immunity over time and can also lead to secondary infections with other microbes ultimately leading to death if not appropriately treated. In some cases, such as influenza virus infection, mortality can be dramatic due in large part to acquired secondary bacterial infections. Many microbes manipulate host immunity and thereby inhibit the ability of patients to combat secondary microbial infections. The overall survival of patients primarily infected with some viruses, parasites, or bacteria, is closely linked to the ability of secondary infections to take advantage of the immune modulation induced by the primary infection. Herein we discuss some of the secondary immune defects caused by select viruses (measles, influenza, HIV1, HTLV), parasites, (leishmania, malaria), and bacteria (Bordetella pertussis). Furthermore, the genetic susceptibility of a given host to become infected, or develop severe disease, also determines whether an infected individual who becomes infected with a secondary microbe survives. Future studies are needed to explore not only the immunomodulation caused by select microbes, but also the repertoire of immune responses expressed by infected individuals in order to predict clinical outcomes of these infections. Thus, understanding the delicate balance that exists between “immune altering” microbes that suppress immune responses during primary infections leading to severe secondary infections versus those infections found in patients with inborn errors of innate or adaptive immunity, is essential in predicting the clinical outcome and the appropriate treatment for these two different patient populations.