Rituximab, an anti-CD20 monoclonal antibody (mAb), is indicated in the treatment of B-cell non-Hodgkin lymphomas, chronic lymphoid leukemia, and rheumatoid arthritis. The occurrence of infusion-related reactions (IRR), especially during the first infusion, is one of the main concerns of rituximab, otherwise well tolerated. Although IRR are usually mild to moderate, fatal evolutions have been reported. These reactions are not specific to rituximab and also observed with other compounds, including those recruiting effectors cells. Further studies are required to predict the frequency and severity of such reactions, to avoid life-threatening complications, especially in the first-in-human studies. Areas covered: This review reports data available to date on the occurrence of IRR induced by rituximab. Then, factors associated with IRR are described, with proposed pathogenic mechanisms of IRR. Finally, different methods to prevent and manage IRR are reported. Expert opinion: Various factors have been associated with the occurrence and severity of IRR. A predictive model of IRR is of importance to prevent life-threatening IRR or detrimental interruption of rituximab therapy. This model would combine parameters, such as the number of CD20 positive cells and NK cells (CD16 positive), together with the level of CD20 and CD16 expressions, and FCGR3Apolymorphism.