Care of patients with potential CDI can involve isolation and use of antibiotics, often before a definitive diagnosis is available, impacting healthcare resource and contributing to antibiotic resistance. There is anecdotal evidence that the faeces of CDI patients have a distinctive odour, while it is well-established that changes in the gut microbiota are associated with changes in the volatile organic compounds (VOC) produced. A total of twenty-four candidate volatile biomarkers were identified from a review of the literature including in vitro, animal and human studies. Using thermal desorption-gas chromatography-time-of flight mass spectrometry (TD-GC-ToFMS), VOC emission rates were determined on stored frozen stool samples from 53 CDI-positive and 53 CDI-negative patients with unexplained diarrhoea which had previously been diagnosed using enzymatic and nucleic acid amplification tests. Sample preparation was limited to placement of a subsample in an appropriate container. Compounds exhibiting a statistically significant difference (p < 0.05) in emission rate between the CDI-positive and-negative groups and a corresponding area under the receiver-operator characteristic curve (ROC) >0.7 were considered potentially indicative of CDI. Seven compounds were so identified: propan-1-ol (ROC 0.75), 3-methylbutanal (ROC 0.84), ethyl propionate (ROC 0.81), hexanoic acid (ROC 0.73), 4-methylphenol (ROC 0.81), dodecane (ROC 0.80) and indole (ROC 0.85). A number of potential volatile biomarkers of CDI can be sampled rapidly and with little prior preparation from faecal samples of patients with diarrhoea. Of these 4-methylphenol (p-cresol) is of particular interest as it has been anecdotally linked to CDI and is closely related to the biology and virulence of Clostridium difficile. This approach shows promise for the rapid, point-of-care diagnosis of CDI with good sensitivity and specificity.