The clinical response to traditional disease-modifying anti-rheumatic drugs (DMARDs) in indigent South Africans with early rheumatoid arthritis was investigated. A cohort of patients with early (≤2 years) RA who were DMARD-naïve at inception were prospectively assessed for response to DMARDs using the Simplified Disease Activity Index (SDAI) over a 12-month period. Patients with low disease activity (LDA) at 12 months were compared to those with moderate and high disease activity with respect to demographic, clinical, autoantibody and radiographic features. The 171 patients (140 females) had a mean (SD) age of 47.1 (12.4) years, symptom duration of 11.7 (7.1) months and baseline SDAI of 39.4 (16.2). There was a significant overall improvement in the SDAI and its components in the 134 (78.4%) patients who completed the 12 months visit, but only 28.4% of them achieved LDA. The majority of patients (91%) were treated with methotrexate as monotherapy or in combination with chloroquine and/or sulphasalazine. Baseline features that independently predicted a LDA state at 12 months were lower Health Assessment Questionnaire Disability Index (p = 0.023) and a higher haemoglobin level (p = 0.048). Receiver operating characteristic curve analysis showed that the 6-month SDAI was better than the baseline SDAI in predicting the 12-month SDAI (area under the curve of 0.69 vs. 0.52, respectively, p = 0.008). In conclusion, less than a third of the patients achieved a low disease activity at 12 months on traditional DMARDs. Patients who have an inadequate response to traditional DMARDs at 6 months are unlikely to show further improvement on traditional DMARDs at 12 months. These findings underscore the need for better disease control by an aggressive tight control strategy, including intense patient education and biologic therapy.