Clostridium difficile is the leading cause of infectious diarrhea in hospitalized patients. Integrating several infection control and prevention methods is a burgeoning strategy for reducing disease incidence in healthcare settings. We present an up-to-date review of the literature on 'control bundles' used to mitigate the transmission of this pathogen. All clinical studies of control bundles reported substantial reductions in disease rates, in the order of 33%-61%. Using a biologically realistic mathematical model we then simulated the efficacy of different combinations of the most prominent control methods: stricter antimicrobial stewardship; the administering of probiotics/intestinal microbiota transplantation; and improved hygiene and sanitation. We also assessed the health gains that can be expected from reducing the average length of stay of inpatients. In terms of reducing the rates of colonization, all combinations had the potential to give rise to marked improvements. For example, halving the number of inpatients on broad-spectrum antimicrobials combined with prescribing probiotics or intestinal microbiota transplantation could cut pathogen carriage by two-thirds. However, in terms of symptomatic disease incidence reduction, antimicrobials, probiotics and intestinal microbiota transplantation proved substantially less effective. Eliminating within-ward transmission by improving sanitation and reducing average length of stay (from six to three days) yielded the most potent symptomatic infection control combination, cutting rates down from three to less than one per 1000 hospital bed days. Both the empirical and theoretical exploration of C. difficile control combinations presented in the current study highlights the potential gains that can be achieved through strategically integrated infection control. © 2014 SSCC.