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Abstract In insects and other invertebrates, prior pathogen exposures can improve immune responses and survival to subsequent infections through immune priming. Alternatively, stress and metabolic costs of multiple infections can impair host immunity and survival. The effects of high‐temperature extremes on host–pathogen interactions are not well understood despite the increasing occurrence of heat waves caused by climate change.The response of insects to heat waves and pathogens depends on recent evolutionary history with selective pressures. Domestication of insect pests has occurred in lab colonies of model species, reducing selective pressures for immune and heat stress responses. Lab strains are often used in immunological or heat stress experiments to represent wild field strains, but the efficacy of this approach is seldom evaluated.Using the tobacco hornworm (Manduca sexta), we tested the impact of a heat wave during initial pathogen exposure on survival of a secondary infection withBacillus thuringiensisbacteria. We used a domesticated lab population and a naturally occurring field population ofM. sextato evaluate the impacts of recent domestication on immune and thermal responses.A heat wave during initial infection significantly increased survival of the secondaryB. thuringiensisinfection in the field, but not the lab population ofM. sexta.In the field population, survival of the repeated infection was temperature dependent: exposure to an initial infection event reduced survival of the secondary infection at the control temperature regime, consistent with a stress effect. However, a heat wave during the initial infection event increased survival of the secondary infection, consistent with immune priming effects.The results of this study demonstrate that (a) insect response to thermal stress and pathogens can depend on recent domestication and (b) responses of hosts to repeat pathogen exposures can be temperature‐dependent, suggesting that cross‐talk between the heat stress and immune memory pathways may have important consequences for host–pathogen outcomes under heat wave events. Read the freePlain Language Summaryfor this article on the Journal blog.