Melatonin is reported to be an anti-inflammatory agent. No genetic study concerning the association between melatonin and inflammatory disease has yet been reported. Here we performed a polymorphism study on the melatonin receptor type 1B (MTNR1B) in Korean rheumatoid arthritis (RA) patients and controls. The polymorphism of MTNR1B located in 3'-untranslated region (rs 1562444) was selected for its higher rate of heterozygosity among other single nucleotide polymorphisms (SNPs) in both MTNR1A and MTNR1B genes and investigated in RA patients (n = 173) and healthy controls (n = 195) by polymerase chain reaction-restriction fragment length polymorphism assay using NlaIII restriction enzyme. No statistically significant difference in either genotype distribution or allele frequency was observed between RA patients and controls. The genotype distributions and allele frequencies of rheumatoid factor negative [RF(-)] patients were similar to those of controls. However, statistical analysis of genotype revealed a significant association (chi2 = 6.42, P = 0.04) is present between RF(+) and MTNR1B SNP (rs 1562444). Although no statistically significant difference in allele frequency between RF(+) and controls was observed (chi2 = 2.75, P = 0.10), the results might suggest that MTNR1B SNP (rs 1562444) is associated with the presence of RF in RA. This is the first study, to our knowledge, to report a positive genetic relationship between melatonin and RA.