Clostridioides difficile infections primarily affect elderly, hospitalised patients treated with antibiotics and are among the most common healthcare-related infections. This thesis aimed to improve the understanding of the best prevention strategies for this disease, particularly in a Swedish setting. In Paper I, we evaluated the effects of an antibiotic stewardship programme. C. difficile infection incidence fell after a substantial reduction of cephalosporin use at the hospital. No significant change in incidence was seen at a comparable hospital where no stewardship programme was implemented. In Paper II, we evaluated two surveillance algorithms intended to detect outbreaks. None of these could accurately discriminate transmission events. We combined different typing methods with epidemiological links to determine the frequency of intrahospital disease transmission. Transmissions occurred infrequently in our setting. In Paper III, we constructed a mathematical, compartmental model of C. difficile transmission dynamics, where the environmental reservoir of C. difficile spores was modelled alongside patient compartments. Antibiotic stewardship had the largest potential for decreasing infections, while improved cleaning and disinfection practices could best decrease colonisations and environmental spores. Improved isolation had modest effects overall. In conclusion, antibiotic stewardship, directed primarily at cephalosporins, is effective to reduce C. difficile infections in a real-life as well as a modelled Swedish setting. For optimal surveillance and outbreak detection, there is a need to further develop and validate methods. Improved general cleaning and disinfection in hospitals can potentially prevent colonisation and infections if a substantially increased rate of spore reduction is achieved. Such measures may be more important than isolation of infected patients.