Clostridium difficile is a significant nosocomial pathogen and a major cause of antibiotic-associated diarrhoea. C. difficile infection (CDI) is dependent on faecal shedding of hardy spores which persist in the environment. Once ingested by susceptible individuals, spores transit the gastrointestinal tract and germinate in the anaerobic environment of the colon. The resulting vegetative cells colonise the host and produce two major toxins that cause disease. The incidence of CDI has escalated in the last decade, largely due to the emergence of ‘hypervirulent’ strains, which are resistant to fluoroquinolones and have an increased capacity to cause severe disease. Standard antibiotic treatment does not allow the protective gut microbiota to be re-established, leaving patients susceptible to disease relapse. Therefore there is an urgent need for novel therapeutics that do not disrupt resident gut microbiota. Passive immunotherapies, including bovine colostrum, have shown promise in preliminary animal and human clinical trials. Bovine colostrum contains concentrated antibodies and protective compounds, which can be administered to patients orally. Immunising cows during gestation with specific antigens results in high titres of specific antibodies. Importantly, bovine colostrum is attractive for treating CDI as it allows the restoration of commensal gut microbiota. We have shown that cows immunised with inactivated vegetative cells produce colostrum antibodies that react with C. difficile surface proteins, in particular SlpA, the major S-layer component. Furthermore, the antibodies cross-react with a wide range of human and animal isolates. Alongside the vegetative cells, we have also generated colostrum against the spores and toxins and have tested their efficacy in preventing disease in a mouse model of CDI. Prophylactic administration of vegetative cell, spore and toxin colostrum in mixed ratios, to animals infected with C. difficile, has resulted in increased survival and reduced disease severity. These results show that bovine colostrum is an effective immunotherapeutic for the prevention of CDI.