Hemoglobin C (HbC) has been recently associated with protection against Plasmodium falciparum malaria. It is thought that HbC influences the development of immune responses against malaria, suggesting that the variation at the HbC locus (rs33930165) may interact with polymorphic sites in immune genes. We investigated, in 198 individuals belonging to 34 families living in Burkina Faso, statistical interactions between HbC and 11 polymorphisms within interleukin-4 (IL4), IL12B, NCR3, tumor necrosis factor (TNF) and lymphotoxin-α (LTA), which have been previously associated with malaria-related phenotypes. We searched for multilocus interactions by using the pedigree-based generalized multifactor dimensionality reduction approach. We detected 29 multilocus interactions for mild malaria, maximum parasitemia or asymptomatic parasitemia after correcting for multiple tests. All the single-nucleotide polymorphisms studied are included in several multilocus models. Nevertheless, most of the significant multilocus models included IL12B 3' untranslated region, IL12Bpro or LTA+80, suggesting that those polymorphisms play a particular role in the interactions detected. Moreover, we identified six multilocus models involving NCR3 that encodes the activating natural killer (NK) receptor NKp30, suggesting an interaction between HbC and genes involved in the activation of NK cells. More generally, our findings suggest an interaction between HbC and genes influencing the activation of effector cells for phenotypes related to mild malaria.