Anthrax lethal toxin (LT) is cytotoxic to macrophages from certain inbred mouse strains. The gene controlling macrophage susceptibility to LT is Nalp1b. Nalp1b forms part of the inflammasome, a multiprotein complex involved in caspase‐1 activation and release of interleukin (IL)‐1β and IL‐18. We confirm the role of caspase‐1 in LT‐mediated death by showing that caspase inhibitors differentially protected cells against LT, with the degree of protection corresponding to each compound's ability to inhibit caspase‐1. Caspase‐1 activation and cytokine processing and release were late events inhibited by elevated levels of KCl and sucrose, by potassium channel blockers, and by proteasome inhibitors, suggesting that inflammasome formation requires a protein‐degradation event and occurs downstream of LT‐mediated potassium efflux. In addition, IL‐18 and IL‐1β release was dependent on cell death, indicating that caspase‐1‐mediated cytotoxicity is independent of these cytokines. Finally, inducing NALP3‐inflammasome formation in LT‐resistant macrophages did not sensitize cells to LT, suggesting that general caspase‐1 activation cannot account for sensitivity to LT and that a Nalp1b‐mediated event is specifically required for death. Our data indicate that inflammasome formation is a contributing, but not initiating, event in LT‐mediated cytotoxicity and that earlier LT‐mediated events leading to ion fluxes are required for death.