Rituximab (RTX), a monoclonal antibody against CD20, is known to cause fewer side effects than conventional anti-cancer drugs; however, infusion reaction (IR), which is specific to monoclonal antibody therapy, is frequently triggered by RTX. Therefore, we designed this study to identify risk factors based on clinical test values for developing IR after RTX administration. Eighty-nine patients with B-cell non-Hodgkin's lymphoma who had received RTX for the first time between February 2010 and March 2013, at the Gifu Municipal Hospital were enrolled as subjects. Analysis of data was conducted for 87 patients, after excluding patients whose data were missing. Univariate analysis showed significant differences in the number of patients exhibiting a soluble interleukin-2 receptor (sLL-2R) level > 2,000 U/L and hemoglobin (Hb) < lower standard limit (LSL) between the IR and non-IR groups. Multivariate analysis showed significant differences with respect to slL-2R > 2,000 U/L [odds ratio (OR), 4.463; 95% confidence interval (Cl), 1.262-15.779; P = 0.020], Hb < LSL [OR, 3.568; 95% CI, 1.071-11.890; P = 0.038], and steroid administration [OR, 0.284; 95% Cl, 0.094-0.852; P = 0.025]. Our findings show that sIL-2R > 2,000 U/L, Hb < LSL, and a lack of steroid premedication are risk factors for developing IR following RTX treatment.