Background. Human ficolin-2 (L-ficolins) encoded by the FCN2 gene are pattern-recognition proteins involved in innate immunity and are associated with several infectious diseases. Methods. A Nigerian cohort of 168 Schistosoma haematobium–infected individuals and 192 healthy controls were examined for functional single-nucleotide polymorphisms in the promoter region (−986G>A, −602G>A, −4A>G) and in exon 8 (+6424G>T) using real-time polymerase chain reaction. Results. The FCN2 −986A and −4G alleles were significantly associated with the occurrence of schistosomiasis (P = .0004 for −986G>A; P = .0001 for −4A>G). The heterozygous genotypes (P = .0006 for −986G>A; P = .0002 for −4A>G) were observed to be a risk factor for susceptibility to schistosomiasis, whereas the homozygous genotypes of major alleles (P = .0002 for −986G>A; P = .0001 for −4A>G) were observed to shield against schistosomiasis. The haplotype AGGG (P = .0002) was observed to be a risk factor for susceptibility to schistosomiasis compared with controls, and the haplotype GGAG (P = .04) was observed to confer protection compared with patients. Ficolin-2 serum level was significantly higher in controls (P < .005) and in controls with GGAG haplotypes (P < .0001). Conclusions. Our findings demonstrate that FCN2 promoter variants (−986G>A and −4A>G) influence ficolin-2 serum levels and susceptibility to schistosomiasis.