Clostridium difficile diarrhoea is an urgent threat to patients, but little is known about the role of antibiotic administration that starts in emergency department observation units (EDOUs). We studied risk factors for antibiotic-associated diarrhoea (AAD) and C. difficile infection (CDI) in EDOU patients. This prospective cohort study enrolled adult patients discharged after EDOU antibiotic treatment between January 2013 and 2014. We obtained medical histories, EDOU treatment and occurrence of AAD and CDI over 28 days after discharge. We enrolled and followed 275 patients treated with antibiotics in the EDOU. We found that 52 (18.6%) developed AAD and four (1.5%) had CDI. Patients treated with vancomycin [relative risk (RR) 0.52, 95% confidence interval (CI) 0.3-0.9] were less likely to develop AAD. History of developing diarrhoea with antibiotics (RR 3.11, 95% CI 1.92-5.03) and currently failing antibiotics (RR 1.90, 95% CI 1.14-3.16) were also predictors of AAD. Patients with CDI were likely to be treated with clindamycin. In conclusion, AAD occurred in almost 20% of EDOU patients with risk factors including a previous history of diarrhoea with antibiotics and prior antibiotic therapy, while the risk of AAD was lower in patients receiving treatment regimens utilizing intravenous vancomycin.