The rate of mortality from Clostridium difficile infection (CDI) between 1999 and 2004 has dramatically increased. The Centers for Disease Control and Prevention reported a 6-fold increase in deaths associated with CDI compared with all other gastrointestinal (GI) tract infections combined. Septicemia, renal failure, pneumonia, urinary tract infection, and anemia were the most frequent conditions of CDI-associated deaths. Coinfections occurring with Giardia lamblia, vancomycin-resistant Enterococcus, and Pseudomonas have been previously reported. However, coinfection with zygomycete organisms has not been reported. We report 2 elderly patients who presented with severe diarrhea and positive C difficile toxin and were refractory to medical management that required colectomies. The histopathologic findings were consistent with CDI, and invasive zygomycetes were incidentally discovered.