Several lines of evidence point to the relevance of epistatic effects in the etiology of complex diseases but, up to now, no studies have been carried out to analyze the presence of SNP-SNP interactions in IPA infection. For this reason, we decide to assess interactions among genetic polymorphisms within DC-SIGN, Dectin-1, Dectin-2, CCL2 and CCR2, genes and the risk of IPA infection. The MDR approach used in this study was able to determine two multilocus combinations associated with high risk to develop IPA infection. Of the interactions identified, MDR indicated that the type of interaction in the two significant models was synergistic. These results support the hypothesis that multiple SNP-SNP interactions may play a role in determining the risk of IPA infection. This hypothesis is biologically plausible since the immune system would warrant prevention of fungal infection even when some genetic variants were present.