Despite aggressive treatment for systemic lupus erythematosus (SLE) with high-dose glucocorticoids and immunosuppressive agents, a significant proportion of patients persist with activity or relapse. Although the results from randomized studies showed no beneficial effects of rituximab (RTX) in SLE, this treatment has proven promising results in open label trials including patients with severe and refractory disease. We report a prospective cohort of 42 Colombian patients with severe and refractory SLE treated with RTX after failure response to glucocorticoids and, at least, another immunosuppressive drug. We observed a reduction in steroid requirement [47.4 mg/day at 24 months (p < 0.001)]. Since the first three-month follow-up, 28% and 36% of the patients fulfilled criteria of complete or partial remission according to proteinuria, and 12.5% and 33% according to creatinine clearance, respectively. These response criteria remained at 12 months. Both neuropsychiatric and hematological sub-groups had a favorable clinical response. The median reinfusion-free survival time was 44 months (95% confidence interval: 10.1-50.1) and 80% of the patients did not require RTX reinfusion. Eleven adverse events were reported in 28 subjects. Most of these occurred during the first three-month follow-up, time during which patients were exposed to high-dose glucocorticoids.