Introduction: 90Y-Zevalin labeling may cause severe finger radiation exposure, especially in high-dose protocols (HD-Zevalin), where up to 7.4 GBq could be injected. In this work, we optimized the labeling of HD-Zevalin with special regard to simplicity, speed, safety and radiation protection. Methods: Factors influencing labeling outcome (activity, specific activity, time, final volume, stability) were studied separately. The critical steps of a standard radiolabeling procedure were optimized to reduce finger exposure, developing an alternative labeling procedure and including a different 90Y supplier. Finger doses were monitored by thermoluminescent dosimeters at each fingertip under anti-X gloves, considering both absolute values and values after normalization to 1.48 GBq. Results: Labeling of 90Y-Zevalin was safe and reproducible up to 7.4 GBq with a simple and single-step procedure offering good stability for several hours. Radiolabeling specific activity was found critical, being kept at 740 MBq·mg-1. Radiochemical purity values ≥98% were routinely achieved. The alternative procedure allowed a sensible reduction of finger dose, due to both the different 90Y vial and the handling. Finger exposure was reduced from 6.6±4.3 to 3.1±0.8 mSv/1.48 GBq in the case of the original 90Y vial and from 1.5±0.9 to 0.3±0.1 mSv/1.48 GBq using a shielded 90Y vial. Conclusions: HD-Zevalin can be prepared in a safe and reproducible way, giving high radiochemical purity values, good stability and low finger exposure. This study may improve the safety of nuclear medicine professionals involved in the preparation of Zevalin. © 2010 Elsevier Inc. All rights reserved.