Biosimilars offer cost-effective and safe treatment options both for patients and healthcare systems. CT-P10 is the first biosimilar of rituximab approved in Europe for use in all indications of originator rituximab (oRTX). This study aimed to provide real-life data on treatment changes and adverse events in patients who received oRTX or CT-P10. We retrospectively reviewed treatment-related adverse events [infusion-related reactions (IRRs), infections, hypogammaglobulinemia] in patients treated with at least one dose of oRTX (MabThera) or CT-P10 (Truxima) between 2020 and 2021 and had at least 6 months follow-up after rituximab infusion in a rheumatology clinic. The switches between oRTX and CT-P10 were performed according to drug availability at the hospital pharmacy at the time of infusion according to the local hospital procedure. Physicians were not involved in the decision of biosimilar selection. A total of 128 patients (CT-P10, n = 64; oRTX, n = 64) were included. CT-P10 was switched in 52 (40.6%) patients who had previously used oRTX, and 48 (37.5%) patients remained on oRTX. We demonstrated no difference between patients treated with oRTX or CT-P10 in the rates of IRRs, in which all reactions were grade 1 and 2. Comparable rates of infections (p > 0.05) and the rate of hypogammaglobulinemia (p > 0.05) were found in both groups with no significant difference. CT-P10 provides a safe treatment alternative in patients who require rituximab therapy. The rational use of biosimilars can be supported by evolving evidence on interchangeability and switching in real-life settings, which will help clinicians in decision-making.