The risk of pneumococcal infection is much increased in persons with impaired IgG synthesis, impaired phagocytosis, or defective clearance of pneumococci. In particular, the absence of a functional spleen, through congenital asplenia, splenectomy, or sickle-cell disease predisposes one to a more severe course of infection (Overwhelming post-splenectomy infection) and prevention measures are indicated (see asplenia). S. pneumoniae expresses different virulence factors on its cell surface and inside the organism. These virulence factors contribute to some of the clinical manifestations during infection with S. pneumoniae.

People whose immune system is compromised, such as those living with HIV, are also at higher risk of pneumococcal disease.^[1] In HIV patients with access to treatment, the risk of invasive pneumoccal disease is 0.2%-1% per year and has a fatality rate of 8%.^[1]

There is an association between pneumococcal pneumonia and influenza.^[2] Damage to the lining of the airways (respiratory epithelium) caused by influenza may facilitate pneumococcal entry and infection.

Other risk factors include smoking, injection drug use, Hepatitis C, and COPD.^[1]