Antimicrobial peptides act as a host defense mechanism and regulate the commensal microbiome.To obtain a comprehensive view of genes contributing to long-term memory we performed mRNA sequencing from single Drosophila heads following behavioral training that produces long-lasting memory. Surprisingly, we find that two immune peptides with antimicrobial activity, Diptericin B and Gram-Negative Bacteria Binding Protein like 3, regulate long-term but not short-term memory or instinctive behavior in Drosophila. The cellular requirement of these two peptides is distinct: head fat body for DptB, and neurons for GNBP-like3. That antimicrobial peptides influence memory provides a novel example of the emerging link between the immune and nervous systems and reveals that some immune peptides may have been repurposed in the nervous system. Author summaryIt is becoming evident that the nervous system and immune system share not only some of the same molecular logic but also the same components. Here, we report a novel and unanticipated example of how immune genes influence nervous system function. During exploring how Drosophila form longlasting memories of certain experiences, we have found that antimicrobial peptides that fight bacteria in the body, are expressed in the head, and control whether an animal would form long-term memory of a food source or a mating partner. Antimicrobial peptides are detected in the brain of many species and has often been associated with dysfunction of the nervous system. This and other recent works, provide an explanation to why antimicrobial peptides may be expressed in the brain: they regulate normal functions of the brain. Both eating, and mating engage the immune system in preparation of exposure to external agents including bacteria. We speculate antimicrobial peptides were upregulated in the body to deal with immune challenges and over evolutionary time some of them are co-adopted to convey specific information about food or mating to the brain.