Heparan sulfate proteoglycans (HSPGs) located at the cell surface and in the extracellular matrix of most animal tissues are proteoglycan coreceptors that carry heparan sulfate chains, and play a vital role in infections of many diseases. HSPGs are classified as glypican, syndecan, perlecan and agrin according to different core proteins. Syndecan-2 (SDC2) is one of the four coding genes of syndecan, while heparan sulfate proteoglycan 2 (HSPG2) is for perlecan. In this study, we cloned the cDNA of porcine SDC2 and analyzed its genomic structure. The porcine SDC2 and HSPG2 were mapped to SSC4p12-13 and SSC6q24-25 by the SCHP panel respectively, further IMpRH panel analysis showed that they were most closely linked to the marker SWR362 and SW709. One special domain named the 4.1 m domain (putative band 4.1 homologues' binding motif) was found in the prediction amino acid sequence of porcine SDC2. RT-PCR showed that both of porcine SDC2 and HSPG2 were expressed widely in detected tissues: heart, liver, spleen, lung, kidney, stomach, muscle, fat and lymph. Upon stimulation in healthy Tongcheng piglets with PRRSV, SDC2 mRNA did not induce a prominent change in the PAMs, while HSPG2 mRNA displayed a dramatic decline. In addition, synonymous mutation g.32A>G of the SDC2 gene was detected and confirmed to be significantly associated with hematocrit, mean corpuscular volume and hemoglobin concentration in the peripheral blood (p < 0.05). A single nucleotide polymorphism g.83.A>G was found in the HSPG2 gene and the association analysis showed that it was significantly associated with mean corpuscular hemoglobin (p < 0.05). Our results confirmed the relation of porcine SDC2 and HSPG2 to the immunity in pigs, and these two genes could be used as candidate genes for improving immune traits in industrial pig breeding.