Objective. Restricted T cell receptor (TCR) gene usage has been demonstrated in animal models of autoimmune disease and has resulted in the successful use of TCR peptide therapy in animal studies. This clinical trial was undertaken to determine the safety and efficacy of a combination of V(β)3, V(β)14, and V(β)17 TCR peptides in Freund's incomplete adjuvant (IFA) in patients with rheumatoid arthritis (RA). Methods. A double, blind, placebo-controlled, multicenter, phase II clinical trial was undertaken using IR501 therapeutic vaccine, which consists of a combination of 3 peptides derived from TCRs (V(β)3, V(β)14, and V(β)17) in IFA. A total of 99 patients with active RA received either 90 μg (n = 31) or 300 μg (n = 35) of IR501 or IFA alone (n = 33) as a control. The study medication and placebo were administered as a single intramuscular injection (1 ml) at weeks 0, 4, 8, and 20. Results. Treatment with IR501 was safe and well tolerated. None of the patients discontinued the trial because of treatment-related adverse events. Efficacy was measured according to the American College of Rheumatology 20% improvement criteria. Using these criteria, patients in both IR501 dosage groups showed improvement in disease activity. In the most conservative analysis used to evaluate efficacy, an intent-to-treat analysis including all patients who enrolled, the 90-μg dosage group showed a statistically significant improvement compared with control patients at the 20-week time point after the third injection. Trends toward improvement were shown in both the 90-μg and the 300-μg dosage groups at week 24 after the fourth injection. Conclusion. IR501 therapeutic vaccine therapy was safe and well tolerated, immnnogenic, and demonstrated clinical improvement in RA patients. Additional clinical trials are planned to confirm and extend these observations.