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★ Caudal-silenced mosquitoes have enhanced resistance to Plasmodium falciparum infection. ★ Caudal regulates the mosquito midgut microbiota. ★ Silencing of Caudal enhanced resistance to systemic bacterial infections. ★ Caudal-silenced mosquitoes live longer but have impaired fecundity and fertility.Malaria parasite transmission depends upon the successful development of Plasmodium in its Anopheles mosquito vector. The mosquito's innate immune system constitutes a major bottleneck for parasite population growth. We show here that in Anopheles gambiae, the midgut-specific transcription factor Caudal acts as a negative regulator in the Imd pathway-mediated immune response against the human malaria parasite Plasmodium falciparum. Caudal also modulates the mosquito midgut bacterial flora. RNAi-mediated silencing of Caudal enhanced the mosquito's resistance to bacterial infections and increased the transcriptional abundance of key immune effector genes. Interestingly, Caudal's silencing resulted in an increased lifespan of the mosquito, while it impaired reproductive fitness with respect to egg laying and hatching.