Objective. Tumor necrosis factor α (TNFα) is among the most prominent cytokines in rheumatoid arthritis (RA) and is secreted mainly by macrophages. A direct method for restoring the immunologic balance in RA is use of small interfering RNA (siRNA) for silencing the TNFα transcript. The aim of this study was to determine the therapeutic effect of systemic administration of TNFα siRNA in an experimental model of RA, optimizing its delivery using new liposome formulations. Methods. Murine macrophages were transfected with siRNA targeting TNFα, and expression was measured. The therapeutic effect in collagen-induced arthritis (CIA) was assessed after intravenous delivery of TNFα siRNA. Delivery was optimized using a carrier DNA for complexation with the cationic liposome RPM209120/DOPE. Levels of TNFα and other cytokines were measured in sera and joint tissue-conditioned media. Biodistribution was determined using a fluorescent siRNA. Results. In vitro, TNFα siRNA efficiently and specifically modulated the expression of TNFα at both the messenger RNA and protein levels. In vivo, complete cure of CIA was observed when TNFα siRNA was administered weekly, complexed with the liposome and combined with carrier DNA. Inhibition (50-70%) of articular and systemic TNFα secretion was detected in the siRNA-injected groups, which correlated with a decrease in the levels of interleukin-6 and monocyte chemotactic protein 1. The main organs targeted by siRNA were the liver and spleen; the addition of liposome RPM209120 and carrier DNA significantly increased organ uptake. Conclusion. We demonstrated the efficiency of systemic delivery of siRNA designed to silence TNFα in CIA, using a liposome carrier system as a way to address the methodologic limitations in vivo.