Antimicrobial peptides (AMPs) are key players in innate defence against infection in plants and animals. In Drosophila, many host defence peptides are produced downstream of the Toll and Imd NF-κB pathways. Use of single and compound AMP mutations in Drosophila has revealed that AMPs can additively or synergistically contribute to combat pathogens in vivo. However, these studies also revealed a high degree of specificity, wherein just one AMP can play a major role in combatting a specific pathogen. We recently uncovered a specific importance of the antibacterial peptide Drosocin for defence against Enterobacter cloacae. Here, we show that the Drosocin locus (CG10816) is more complex than previously described. In addition to its namesake peptide “Drosocin”, it encodes a second peptide generated from a precursor via furin cleavage. We name this peptide “Buletin”, and show that it corresponds to the uncharacterized “Immune-induced Molecule 7” previously identified by MALDI-TOF. The existence of a naturally occurring polymorphism (Thr52Ala) in the CG10816 precursor protein masked the identification of this peptide previously. Using mutations differently affecting the production of these two CG10816 gene products, we show that Drosocin, but not Buletin, contributes to the CG10816-mediated defence against E. cloacae. Strikingly, we observed that Buletin, but not Drosocin, contributes to the CG10816-mediated defence against Providencia burhodogranariea. Moreover, the Thr52Ala polymorphism in Buletin affects survival to P. burhodogranariea, wherein the Alanine allele confers better defence than the Threonine allele. However, we found no activity of Buletin against either P. burhodogranariea or E. coli in vitro. Collectively, our study reveals that CG10816 encodes not one but two prominent host defence peptides with different specificity against different pathogens. This finding emphasizes the complexity of the Drosophila humoral response consisting of multiple host defence peptides with specific activities, and demonstrates how natural polymorphisms found in Drosophila populations can affect host susceptibility.