Clostridium difficile is a significant nosocomial pathogen and a major cause of antibiotic-associated diarrhea in the developed world. In the last decade, the incidence of C. difficile infections (CDI) has increased, largely due to the emergence of ‘hypervirulent’ BI/NAP1/027 strains. These strains produce increased levels of the two major toxins TcdA and TcdB and appear to have an increased capacity to cause severe disease. In addition, these strains have developed resistance to fluoroquinolone antibiotics and certain macrolides. The current treatment for CDI is the use of vancomycin/metronidazole, however, these antibiotics do not allow for re-establishment of the normal gut microbiota, leaving patients susceptible to relapse. Passive immunotherapy based treatments, including the use of bovine colostrum, have shown promise in preliminary animal and human trials. Bovine colostrum is a pre-milk secretion, containing concentrated antibodies and protective compounds, which can be administered to patients orally. Importantly, preliminary studies have shown that colostrum generated against C. difficile can neutralise toxin and prevent disease relapse. However, further studies are required to determine whether bovine colostrum can be used prophylactically to prevent or treat fulminant disease, particularly CDI associated with BI/NAP1/027 C. difficile isolates. This study examines the use of vegetative cell-specific bovine colostrum for the prevention and treatment of CDI. We have shown that cows immunised with whole inactivated vegetative cells of an Australian BI/NAP1/027 strain produce specific antibodies that react with C. difficile surface proteins, in particular SlpA, the major component of the S-layer. Furthermore, these antibodies cross-react with a wide range of clinically relevant human and animal isolates. Currently, we are testing the efficacy of this colostrum in preventing and treating disease in a mouse model of fulminant CDI. We have shown that pre-treatment of mice with vegetative cell-specific colostrum results in increased survival and reduced severity of disease. This study will lead to the development of novel therapeutic strategies for the prevention of C. difficile infections in the clinic.