This study was intended to evaluate HLA-DRB1 alleles and antibodies against anti-cyclic citrullinated peptides (anti-CCP Abs) for their value in predicting patient responses to treatment with disease-modifying antirheumatic drugs (DMARDs) in early rheumatoid arthritis (RA). The subjects were 124 Japanese patients who had received their first treatment with DMARDs, usually methotrexate, within 1 year of disease onset and who had been followed-up for 2 years subsequently. Approximately 40% of patients developed DMARD resistance and accordingly required anti-tumor necrosis factor α (TNFα) therapy during the 2-year period. DMARD resistance was strongly associated with the carriage of SE-positive HLA-DRB1*04 alleles, especially the *0405 allele (OR, 3.92; 95%CI, 1.83-8.41; p = 0.0003). In contrast, the SE-positive allele HLA-DRB1*0101 was less potent in contributing to DMARD resistance. The rate of anti-CCP Ab-positive patients was significantly higher in the DMARD-resistant group (OR, 6.62; 95%CI, 1.45-30.24; p = 0.008). Multivariate logistic regression analysis confirmed the strong association of DMARD resistance with the presence of SE-positive *04 alleles (OR, 2.89; 95%CI, 1.28-6.53; p = 0.011) and anti-CCP Abs (OR, 6.31; 95%CI, 1.23-32.34; p = 0.027), yielding an area under the receiver operating characteristic curve of 0.76 (95% CI, 0.68-0.84; p = 0.000). After stratification, the highest rate of DMARD resistance was observed in patients having both SE-positive *04 alleles and anti-CCP Abs. These observations show that the presence of SE-positive *04 alleles in combination with anti-CCP Abs is the strongest predictor for development of DMARD resistance and eventual need of anti-TNFα agents in patients with early RA.