Rheumatoid arthritis is a severe, aggressive, and debilitating disease that has a high mortality rate. There have been considerable advances in the last few years as a result of developments in molecular biology, immunology, and biotechnology. The knowledge about the elements that directly participate in the genesis of the disease has been established. Nowadays, treatments are more rational and are directed to specific targets. Anticytokine agents, especially therapies that target tumor necrosis factor (TNF), are considered to be frontline biological agents for the treatment of rheumatoid arthritis. The blocking of lymphocyte B with rituximab, a genetically engineered chimerical monoclonal antibody, has been approved by the US Food and Drug Administration as a treatment in patients with rheumatoid arthritis who have severe disease not responding to conventional multiple therapies and to TNF-blocker agents. We propose that patients with severe aggressive rheumatoid arthritis could benefit from rituximab without previous exposure to anti-TNF agents as a biological agent, and we postulate that rituximab could be used as a first-line biological agent in this subgroup. We present our recent experience with patients having severe and active rheumatoid disease with whom we used rituximab as a first-line biological agent.