Here we describe the biochemical characterization of two C-type lectins, CTL4 and CTLMA2, that play key roles as negative regulators of the melanization cascade in the malaria vector An. gambiae. This is relevant to malaria transmission as knockdown of CTL4 and CTLMA2 results in reduced susceptibility to P. berghei and, with comparable infection levels, P. falciparum. The effect of CTL4 and CTLMA2 on Plasmodium is species-dependent, suggesting divergent evolution of the trait during speciation within the Anopheles genus. Here, SLC44A4 is linked to malaria.