Broad-spectrum antibiotics are often associated with a relatively high risk of Clostridium difficile infection (CDI). However, exceptions to this rule, e.g., piperacillin-tazobactam, show that marked inhibition of gut flora is not synonymous with CDI risk. Tigecycline has marked broad-spectrum activity that includes Gram-positive and Gram-negative facultative and obligate anaerobes. Antibiotic susceptibility, gut model and clinical trial data suggest that tigecycline is associated with a relatively low risk of CDI. Further clinical data should be obtained to confirm the results of these initial studies.