Background: The PTPN22 gene has been widely confirmed as a susceptibility gene for rheumatoid arthritis (RA) in populations of Northern European descent. The aim of the current study was to explore the role of variants spanning the PTPN22 gene in determining susceptibility to and outcome of inflammatory polyarthritis (IP). Patients and methods: Single nucleotide polymorphism (SNP) variants spanning the gene were genotyped using the Sequenom MassArray platform and tested, firstly for their association with susceptibility to IP. Genotype frequencies were compared between new onset IP cases (n = 843) and population controls (n = 471). Secondly, a within-cohort analysis was performed testing each variant for association with a number of clinical outcome measures reflecting disease severity including radiological erosions, physical function, measured using the Health Assessment Questionnaire (HAQ) score, and disease activity at defined time-points following disease presentation. Results: A significant association between carriage of the PTPN22*1858T allele and IP (odds ratio (OR) = 1.4 (95% CI 1.1-1.9), p = 0.02) was observed. The strength of the effect was similar in the RA subgroup (OR = 1.4 (95% CI 1.0-1.9), p = 0.05). No association between IP susceptibility and any of the other SNPs was detected. No association was detected for any of the SNPs tested, including the PTPN22*C1858T polymorphism, for either erosive status, Larsen score by 5 years or other markers of clinical outcome. Conclusion: The PTPN22X1858T polymorphism is associated with susceptibility to IP, but we have found no evidence for association of this or other variants spanning the gene with clinical outcome measures.