Lymphatic filariasis (LF) is a parasitic infection, caused by three closely related nematodes, namely <i>Wuchereria bancrofti</i>, <i>Brugia malayi</i>, and <i>Brugia timori</i>. Previously, we have shown that lysate from <i>B. malayi</i> microfilariae induces the expression of interleukin <i>(IL)-10</i> and programmed death-ligand <i>(PD-L) 1</i> on monocytes, which lead to inhibition of CD4<sup>+</sup> T-cell responses. In this study, we investigated associations of <i>IL-10</i> and programmed cell death <i>(PD)-1</i> pathway gene polymorphisms with clinical manifestation in LF. We evaluated the frequency of alleles and genotypes of <i>IL-10</i> (
rs3024496,
rs1800872), <i>IL-10RA</i> (
rs3135932), <i>IL-10RB</i> (
rs2834167), <i>PD-1</i> (
rs2227982,
rs10204525), <i>PD-L1</i> (
rs4143815), <i>PD-L2</i> (
rs7854413), and single-nucleotide polymorphisms (SNPs) in 103 patients with chronic pathology (CP), such as elephantiasis or hydrocele and 106 endemic normal (EN) individuals from a South Indian population living in an area endemic for LF. Deviations from the Hardy-Weinberg equilibrium were tested, and we found a significant difference between the frequency of polymorphisms in <i>PD-L2</i> (
rs7854413; <i>P</i> < 0.001) and <i>IL-10RB</i> (
rs2834167; <i>P</i> = 0.012) between the CP and the EN group, whereas there were no significant differences found among <i>IL-10</i>, <i>IL-10RA</i>, <i>PD-1</i>, and <i>PD-L1</i> SNPs. A multivariate analysis showed that the existence of a CC genotype in <i>PD-L2</i> SNP
rs7854413 is associated with a higher risk of developing CP (OR: 2.942; 95% confidence interval [CI]: 0.957-9.046; <i>P</i> = 0.06). Altogether, these data indicate that a genetically determined individual difference in a non-synonymous missense SNP of <i>PD-L2</i> might influence the susceptibility to CP.