We investigated associations between the methylenetetrahydrofolate reductase (MTHFR) polymorphisms C677T and A1298C and methotrexate (MTX)-related toxicities in Korean patients with rheumatoid arthritis (RA) taking MTX. One hundred sixty-seven patients with RA were enrolled in a cross-sectional study and genotyped for the single-nucleotide polymorphisms C677T and A1298C in MTHFR. Alleles, genotypes, and haplotypes of the C677T and A1298C polymorphisms were not associated with specific MTX toxicities. However, among RA patients with the 1298CC genotype, the proportion who experienced at least one toxicity was significantly greater than the proportion of patients with 1298AA who did (P = 0.043). In addition, the proportion of patients with the 677C/1298A haplotype who experienced toxicity was greater than the proportion of those with 677C/1298C who did (P = 0.032, odds ratio = 2.085, 95% confidence interval 1.058-4.106). In this study, MTHFR polymorphisms were associated with MTX toxicities in Korean patients with RA. Further study for association of MTHFR polymorphisms with MTX toxicities should be needed in larger RA population.