Background: The role of SET protein (BaSET) in B. anthracis life cycle was unknown until now. Results: BaSET regulates NF-κB activation, septation, and infectivity. Conclusion: BaSET is one of the key effectors for B. anthracis pathogenesis. Significance: Previous studies predict that SET protein may not have any role in lower organisms. Hence, this is the first report demonstrating SET protein function in a human pathogen.