Interleukin 10 (IL-10) is an important anti-inflammatory cytokine that modulates severe periportal fibrosis (PPF). We hypothesized that genetic polymorphisms (-G1082A/-C819T/-C592A) of the IL-10 gene and classic factors (age, sex, alcohol, exposure, and specific treatment) are associated with the severity of PPF and that these polymorphisms influence IL-10 expression. In this cross-sectional study, we genotyped these polymorphisms within the IL-10 gene in 203 Brazilian subjects infected with Schistosoma mansoni, with different patterns of PPF. There was an association of protection between the ages of 41 and 60 years and advanced standard PPF. The -1082AA genotype was significantly associated with severity in PPF when compared with the -1082GG genotype. Similarly, when analyzed together, both the -1082GA+AA genotypes were significantly associated. The ACC and GTA haplotypes indicated a protective effect against PPF, while the ATA haplotype was significantly associated with PPF severity when compared with the GCC haplotype. There was no significant difference between average levels of IL-10 between clinical groups, and there was no association between average serum levels of IL-10 and (-G1082A) IL-10 polymorphism. Our results suggest that (-G1082A) IL-10 polymorphism and putative haplotypes are associated with PPF severity in the Brazilian population.