A new Infection Control and Hospital Epidemiology analysis using six months of intensive surveillance and computational modelling reports that asymptomatic patients account for the overwhelming majority of transmission events that lead to new C. difficile colonizations in oncology wards. Visible symptomatic cases were not the main engine of new colonizations. The findings—derived from modelling of two leukemia and hematopoietic cell transplant units at a large US tertiary hospital—challenge longstanding assumptions that symptomatic infection status best predicts onward spread. For infection prevention programs, this reframes screening and isolation strategies toward colonized but clinically silent patients. The work also underscores the operational value of combining high-frequency surveillance with models that can attribute transmission pathways, offering a blueprint for hospitals trying to reduce secondary infectious complications in immunosuppressed populations.