Vascular endothelial growth factor C (VEGF-C) promotes angiogenesis, a prominent feature in rheumatoid synovitis, contributing to the perpetuation of the global burden of rheumatoid arthritis (RA). VEGF-C gene polymorphisms predict the risk of developing various human diseases, such as urothelial cell carcinoma, oral cancer and coronary artery disease. We sought to determine whether single nucleotide polymorphisms (SNPs) of the VEGF-C gene can predict the risk of RA. Our study recruited 210 patients with RA and 373 healthy controls between 2007 and 2015, and performed comparative genotyping for SNPs rs7664413, rs11947611, rs1485766, rs2046463 and rs3775194. In analyses adjusted for potential covariates, we found that compared with subjects with the A/A genotype of SNP rs11947611, those with the A/G genotype were 40% more likely to develop RA (adjusted odds ratio [AOR] 0.61; 95% confidence interval [CI] 0.40 to 0.92; p = 0.02). In addition, subjects lacking the A/A genotype (A/G, G/G) of SNP rs2046463 were more than twice as likely as those with the A/A genotype to require methotrexate (AOR 2.23, 95% CI 1.25 to 3.98; p = 0.01), while those who lacked the G/G genotype (G/C, C/C) in the SNP rs3775194 had a significantly lower risk of requiring prednisolone as compared with those with the G/G genotype (AOR 0.39, 95% CI 0.19 to 0.79; p = 0.01). Our findings suggest that VEGF-C gene polymorphisms might serve as a diagnostic marker and therapeutic target for RA therapy. Pharmacotherapies that modulate the activity of the VEGF-C gene may be promising for RA treatment.