Here, we show that acute pharmacological inhibition or full genetic deletion of TBK1/IKKε sensitized macrophages to rapid, premature, and excessive death mediated exclusively by enhanced NLRP3, and not RIPK1 signaling, upon infection with the NLRP3-activating pathogen, Listeria monocytogenes. We found the same when macrophages were activated by purified NLRP3 activators, such as the potassium efflux–dependent pore-forming toxin nigericin, the alarmins ATP (adenosine triphosphate) or MSU (monosodium urate), and the potassium efflux–independent TLR7 agonist R837. The gene discussed is RIPK1; the disease is infection.