© 2019 Riegler, Brissac, Gonzalez-Juarbe and Orihuela. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Pore-forming toxin (PFT) induced necroptosis exacerbates pulmonary injury during bacterial pneumonia. However, its role during asymptomatic nasopharyngeal colonization and toward the development of protective immunity was unknown. Using a mouse model of Streptococcus pneumoniae (Spn) asymptomatic colonization, we determined that nasopharyngeal epithelial cells (nEC) died of pneumolysin (Ply)-dependent necroptosis. Mice deficient in MLKL, the necroptosis effector, or challenged with Ply-deficient Spn showed less nEC sloughing, increased neutrophil infiltration, and altered IL-1α, IL-33, CXCL2, IL-17, and IL-6 levels in nasal lavage fluid (NALF). Activated MLKL correlated with increased presence of CD11c+ antigen presenting cells in Spn-associated submucosa. Colonized MLKL KO mice and wildtype mice colonized with Ply-deficient Spn produced less antibody against the bacterial surface protein PspA, were delayed in bacterial clearance, and were more susceptible to a lethal secondary Spn challenge. We conclude that PFT-induced necroptosis is instrumental in the natural development of protective immunity against opportunistic PFT-producing bacterial pathogens.