Objective: To compare the clinical and functional outcome at 2 and 5 years in patients with inflammatory polyarthritis treated with either methotrexate (MTX) or sulfasalazine (SSZ) as the first disease-modifying antirheumatic drug (DMARD). Methods: Patients recruited to a primary-care-based inception cohort of patients with inflammatory polyarthritis were eligible for this analysis if they were started on either SSZ (n = 331) or MTX (n = 108) as their first DMARD within 3 months. Outcomes assessed included the Disease Activity Score (DAS)28, Health Assessment Questionnaire, radiological erosions (Larsen Score) and cumulative mortality with the proportions still on the original treatment. To overcome potential bias in allocation to these two treatments, a propensity score was calculated based on baseline disease status variables. Results are expressed as the mean difference between MTX and SSZ, both unadjusted and adjusted for propensity score. Results: The baseline differences between the two groups disappeared after adjusting for propensity score. At 2 and 5 years there were few differences in the clinical outcomes, either unadjusted or after adjustment for propensity. By contrast, at 5 years the proportion that was erosive was lower in the MTX group: odds ratio 0.3 (95% confidence interval 0.1 to 0.8), with a 31% lower Larsen Score after adjustment. At both time points, those treated with MTX were at least twice as likely to remain on that drug as those treated with SSZ. Conclusion: Long-term clinical outcome is similar in patients prescribed MTX and SSZ, although it would seem that MTX has greater potential to suppress erosions, which supports it being the first DMARD of choice.