Mammals and insects employ similar Rel/NF‐κB signaling cascades in their humoral immune responses. The mammalian interleukin‐1 type I receptor (IL‐1R) is one way of activating this cascade. The Drosophila Toll protein, whose cytoplasmic domain shows striking similarity to that of the IL‐1R, acts in the humoral antimicrobial response. Here we demonstrate that a second IL‐1R‐related Drosophila protein, 18‐Wheeler (18W), is a critical component of the humoral immune response. 18‐wheeler is expressed in the larval fat body, the primary organ of antimicrobial peptide synthesis. In the absence of the 18W receptor, larvae are more susceptible to bacterial infection. Nuclear translocation of the Rel protein Dorsal‐like immunity factor (Dif) is inhibited, though nuclear translocation of another Rel protein, Dorsal, is unaffected. Induction of several antibacterial genes is reduced following infection, relative to wild‐type: attacin is reduced by 95%, cecropin by 65% and diptericin by 12%. Finally, 18‐wheeler (18w) expression is induced in response to infection and, in addition to the receptor form, four immune‐specific transcripts and proteins are produced.