The purpose of this study is to determine factors associated with a non-ACR 50 response at 6 months of follow-up, in a cohort of patients with early rheumatoid arthritis (RA). Early RA patients (symptom duration <1 year), treated with the same combination treatment (methotrexate and sulfasalazine), were included. Demographic characteristics of the patients including current smoker status (defined as a patient that smokes at least one cigarette per day), years of formal education, a 28-joint count for swelling and tenderness were registered. A basal HAQ questionnaire, visual scales for global assessment, and pain were answered by all patients, and a CDAI basal score was calculated. The ACR 50 response was determined at 6 months follow-up. Multivariable logistic regression analysis was used to calculate adjusted ORs. Two hundred twenty-five patients were evaluated, but only 144 had a complete follow-up, 43% of the latter did not reach an ACR 50 response. The only factor associated with this outcome was current smoking (OR 3.58, P < 0.008, 95% CI 1.23-11.22). Low level of formal education (≤6 years) had a tendency towards a statistical difference (P < 0.08). After controlling with low level of formal education, sex, age in years, and CDAI baseline value with multivariable logistic regression analysis, current smoking status had an adjusted OR of 3.91 (P < 0.009, 95% CI 1.41-10.81). Smoking is associated with a non-ACR 50 response in early rheumatoid arthritis in patients treated with a combination therapy with methotrexate and sulfasalazine.