This study focuses on the interaction between an entomopathogenic nematode and an insect model to further investigate the role of parasite body-surface and its compounds (particularly epicuticular lipids) in the immunosuppression of host defences. Our goal was to ascertain the potential interference of the parasite epicuticular lipids with the antimicrobial response mounted by Gram-negative bacteria-challenged hosts. Since the parasite model used in this study (Steinernema feltiae) releases symbiontic bacteria in the host hemocoel during the late phase of infection, the inhibition of the antimicrobial response could be needed to avoid the activity of host factors potentially harmful for the microorganisms. After bacterial challenge, when insect hosts were infected with purified parasite cuticles, we always observed lack of bacterial clearance concurrently with the absence of hemolymph low molecular weight components. The observed effects seem to be related to the interaction of parasite cuticular lipids (PCLs) with specific components of the host hemolymph; these host interacting proteins (HIP17, HIP26 and HIP35) were removed by the parasite, and their absence (or reduction) apparently prevented antimicrobial peptide synthesis. The inhibitory properties were lost when cuticles were pre-treated with compounds (such as lipase or methanol-chloroform) affecting their lipidic moiety. Moreover, the key role of epicuticular lipids was also confirmed by the inhibitory properties of methanol-chloroform extracted lipids, which were comparable to those of parasite whole cuticles. Finally, the involvement of HIPs was assessed by their partial purification followed by injection into the host. When HIPs were co-injected with bacteria into cuticle-inhibited larvae, the antimicrobial activity was completely restored.