To the best of our knowledge, we report the first Clostridium difficile infection in a native hip joint with subsequent prosthetic joint infection in a patient at a state of hypogammaglobulinemia. The infection developed following chemotherapy for B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). After chemotherapy, hip arthroplasty was performed for destructive septic arthritis. However, infection in the hip persisted with several failing revisions for more than 3 years, until ultimately hypogammaglobulinemia and T-/B-lymphocytopenia were diagnosed, and supplementation with i.v. immunoglobulins was able to achieve infection control.