This study genotyped blood samples from 214 patients with rheumatoid arthritis (RA) and 293 healthy controls for single nucleotide polymorphisms (SNPs) rs2977537, rs2929970, rs2929973, rs2977530, rs1689334 and rs62514004. We want to investigate whether the SNPs in the WNT1-inducible signaling pathway protein 1 (WISP-1) gene may increase the risk of developing RA. We showed that RA disease was more likely with the AA genotype compared with the AG genotype of SNP rs2977537 (adjusted odds ratio [AOR]: 0.54; 95% confidence interval [CI]: 0.34-0.84), and with the TT genotype (AOR: 0.24; 95% CI: 0.13-0.39) or the GG genotype (AOR: 0.05; 95% CI: 0.03-0.10) compared with the GT genotype of rs2929973, and with the AA genotype (AOR: 0.34; 95% CI: 0.22-0.54) or GG genotype (AOR: 0.52; 95% CI: 0.31 to 0.87) vs the AG genotype of rs2977530. Rheumatoid factor positivity was more likely with the AA genotype than with the AG genotype of the rs2977537 polymorphism (AOR: 0.16; 95% CI: 0.16-0.94). High CRP (>8 mg/L) was more likely with the non-AG genotype (AA + GG) than the AG genotype of rs2977537 (AOR: 1.84; 95% CI: 1.05-3.21) and with the AA genotype vs the AG genotype of rs2977530 (AOR: 2.62; 95% CI: 1.35-5.09). Compared with the AG genotype, the AA genotype of rs2929970 was more likely to require prednisolone (AOR: 0.49; 95% CI: 0.27-0.88), while the AG genotype was more likely than the AA genotype of SNP rs2977530 to require TNF-α inhibitors (AOR: 2.07; 95% CI: 1.08 to 3.98). WISP-1 may be a diagnostic marker and therapeutic target for RA therapy.