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BACKGROUND [alpha]2-Macroglobulin ([alpha]2-M) has a curative effect on radiation injury. Virus transmission through plasma derivatives is still not risk-free. Effect of dry heat on [alpha]2-M activity and virus inactivation by dry heat in a new manufacturing process of [alpha]2-M were studied. STUDY DESIGN AND METHODS Effects of 100°C for 30 minutes, 80°C for 72 hours, and lyophilization on [alpha]2-M activity were detected, and stabilizing agents were optimized. Effect of a treatment at 100°C for 30 minutes has been tested on a range of viruses and characteristics change of [alpha]2-M was investigated. RESULTS More than 90 and 80% [alpha]2-M activity recovery were reserved after treatment at 100°C for 30 minutes and 80°C for 72 hours, respectively. A concentration of 0.05 mol/L histidine presented a better protecting effect for [alpha]-M activity. No substantial changes were observed in the characteristics of [alpha]2-M compared with the untreated. By lyophilization and dry-heat treatment at 100°C for 30 minutes, murine encephalomyocarditis virus and pseudorabies virus (PRV) were inactivated below detectable level within 5 minutes (virus titers reduction≥5.75 log) and 30 minutes (virus titers reduction≥6.00 log), respectively. Bovine viral diarrhea virus and porcine parvovirus were inactivated by 4.29 and 2.46 log reduction, respectively. CONCLUSION Treatment at 100°C for 30 minutes could improve the virus safety of [alpha]2-M with a slight activity loss.