Immunocompromise is a commonly cited risk factor for Clostridium difficile infection (CDI). We reviewed the experimental and epidemiological literature on CDI in three immunocompromised groups, HIV-seropositive individuals, haematopoietic stem cell or bone marrow transplant recipients and solid organ transplant recipients. All three groups have varying degrees of impairment of humoral immunity, a major factor influencing the outcome of CDI. Soluble HIV proteins such as nef and immunosuppressive agents such as cyclosporin, azathioprine and mycophenalate mofetil modify signalling from the key cellular pathways triggered by C. difficile toxin A, although there is a paucity of data on how these factors may interact with pathways activated by toxin B. Despite this, there has been little direct investigation into the effect of immunosuppression on the pathogenesis of CDI. Epidemiological studies consistently show increased rates of CDI in these populations, which are higher in those with greater degrees of immunocompromise such as individuals with advanced AIDS not receiving combination antiretroviral therapy or allogeneic haematopoietic stem cell transplant recipients. Less consistently data suggests immunocompromise in each group also impacts rates of severe, recurrent or complicated CDI. However all these conditions are characterised by high levels of antibiotic use and prolonged hospital stay, both powerful drivers of CDI risk.