Whole-genome association studies in rheumatoid arthritis have identified single-nucleotide polymorphisms (SNPs) predisposing to disease with moderate risk. We aimed to investigate the role of these markers in predicting methotrexate (MTX) response, measured by continuation on MTX monotherapy in patients with recent onset inflammatory polyarthritis (IP). In all, 19 SNPs were genotyped in 736 patients treated with MTX following registration, or not more than 3 months before registration, to the Norfolk Arthritis Register. The association of SNPs with MTX continuation by year 1 and by year 2 was investigated using Cox proportional hazard regression models. A SNP within the OLIG3/TNFAIP3 locus (rs6920220) was associated with being less likely to maintain MTX monotherapy at year 1, hazards ratio (HR) 1.73 (1.18, 2.52) and year 2, HR 1.49 (1.11, 2.00); correlating with an increased in adverse events. Weak evidence for an effect at the PTPN22 locus was also observed. These findings require replication in other large datasets.