Innate immunity is essential for the survival of organisms across the evolutionary spectrum. Drosophila is well studied as a model of innate immunity and has been instrumental in establishing principles of defense and gene signaling pathways that are shared with humans. Previous studies in Drosophila have not focused on differences between the sexes, and in this report we present evidence that it is essential to include differences between the sexes. Survival rates post-infection, after a fungal or bacterial infection, varied according to the combination of signaling pathway (Toll and Imd) and sex tested. We also found that antimicrobial protein gene mRNA levels for Drosomycin and Metchnikowin showed both similarities and differences between the sexes. These studies highlight the need to include both sexes in studies of immune function as well as the associated opportunities for advancing our understanding of immunity.