Background Clostridioides difficile infection (CDI) is associated with significant morbidity and mortality in both healthcare and community settings. Burden and characteristics of disease are not well defined in Australia. We aimed to define the predisposing factors, risks for severe disease and mortality determinants of CDI in Eastern Australia over a 1-year period. Methods This is an observational retrospective study of CDI in hospitalised patients ≥18 years of age in six tertiary institutions from 1 January 2016 to 31 December 2016. Patients were identified through laboratory databases and medical records of participating institutions. Clinical, imaging and laboratory data was input into an electronic database hosted at a central site. Diagnosis, severity, setting of onset, and recurrence for CDI were defined. Results A total of 578 patients (578 CDI episodes) were included. Median age was 65 years (range, 18 to 99 years) and 48.2% were male. Hospital-onset of CDI occurred in 64.0%. Recent antimicrobial use (41.9%) and proton pump inhibitor use (35.8%) was common. Significant risk factors for severe CDI were age <65 years (P < 0.001), malignancy within the last 5 years (P < 0.001), and surgery within the previous 30 days (P < 0.001). Significant risk factors for first recurrence included severe CDI (P = 0.03) and inflammatory bowel disease (P = 0.04). Metronidazole was the most common regimen for first episodes of CDI with 65.2% being concordant with Australian treatment guidelines overall. Determinants for death at 60 days included age over 65 years (P = 0.01), severe CDI (P < 0.001), and antibiotic use within the prior 30 days (P = 0.02). Of those who received metronidazole as first-line therapy, 10.1% died in the 60-day follow-up period, compared to 9.8% of those who received vancomycin (P = 0.86). Conclusion The burden of CDI is large in Australia and continues to complicate healthcare delivery. Patients who experience CDI are vulnerable and require early diagnosis, clinical surveillance, and effective therapy to prevent complications and improve outcomes.