The bicomponent leukotoxins produced by Staphylococcus aureus kill host immune cells through osmotic lysis by forming ??-barrel pores in the host plasma membrane. The current model for bicomponent pore formation proposes that octameric pores, comprised of two separate secreted polypeptides (S and F subunits), are assembled from water-soluble monomers in the extracellular milieu and multimerize on target cell membranes. However, it has yet to be determined if all staphylococcal bicom- ponent leukotoxin family members exhibit these properties. In this study, we report that leukocidin A/B (LukAB), the most di- vergent member of the leukotoxin family, exists as a heterodimer in solution rather than two separate monomeric subunits. No- tably, this property was found to be associated with enhanced toxin activity. LukAB also differs from the other bicomponent leukotoxins in that the S subunit (LukA) contains 33- and 10-amino-acid extensions at the N and C termini, respectively. Trun- cation mutagenesis revealed that deletion of the N terminus resulted in a modest increase in LukAB cytotoxicity, whereas the deletion of the C terminus rendered the toxin inactive. Within the C terminus of LukA, we identified a glutamic acid at position 323 that is critical for LukAB cytotoxicity. Furthermore, we discovered that this residue is conserved and required for the inter- action between LukAB and its cellular target CD11b. Altogether, these findings provide an in-depth analysis of how LukAB tar- gets neutrophils and identify novel targets suitable for the rational design of anti-LukAB inhibitors.