Clostridioides difficile remains a leading cause of healthcare-associated infection in the United States, with an estimated 500,000 infections annually, and is designated an urgent public health threat by the Centers for Disease Control and Prevention. Traditional surveillance relies on clinical laboratory reporting, which captures only diagnosed cases and provides limited insight into reservoirs and transmission outside patient care areas. Wastewater surveillance has emerged as a population-level tool for tracking enteric pathogens such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and polio, but its relevance to C. difficile epidemiology is uncertain. Although C. difficile has been detected in municipal and hospital wastewater in multiple regions, few studies have directly compared wastewater isolates to clinical strains from the same catchment. Due to the “silent” nature of C. difficile colonization, determining whether wastewater samples capture clinically relevant strains is critical to establishing wastewater surveillance as a complementary approach to infection prevention. We sought to evaluate the genetic relatedness of C. difficile isolates recovered from hospital wastewater to patient clinical isolates identified at the same hospital during the sampling period.