There is a compelling need to identify novel genetic variants for papillary thyroid cancer (PTC) susceptibility. The Cancer Genome Atlas (TCGA) data showed associations between SPP1 and SPARC mRNA overexpression and aggressive behaviors of PTC, which prompted us to assess potential associations between genetic variants in these genes and PTC risk. Three highly linked SPARC loci (rs1054204, rs3210714, and rs3549) contributed to reduced PTC risk under a codominant model (odds ratio [OR], 0.79–0.80). Variant CAG alleles at these loci significantly enhanced SPARC transcription activation upon cotransfection with miR-29b and miR-495 when compared to the common alleles GGC (all P < 0.05). The three SPARC polymorphisms interacted with SPP1 rs4754, with elevated joint ORs of 2.43, 2.52, and 2.52, respectively. Additionally, interaction between SPP1 rs2358744 and SPARC rs2304052 was observed. Our study revealed associations between SPP1 and SPARC polymorphisms that, individually or in combination, are involved in PTC susceptibility. • SPP1 and SPARC expression correlate with papillary thyroid cancer (PTC) stages. • SPARC variants at rs1054204, rs3210714 and rs3549 are related to PTC risk. • SPP1 genotype TT at rs4754 is associated with increased PTC risk. • CAG alleles in the SPARC 3′ UTR reduce the binding affinity of miR-29b and miR-495. • SPP1 rs2358744 and SPARC rs2304052 have an epistatic interaction effect. [ABSTRACT FROM AUTHOR]