ÃÂ±2-Macroglobulin (ÃÂ±2M) is a major human blood glycoprotein best known for its ability to inhibit a broad spectrum of proteases by a unique trapping method. This action induces an activated conformation of ÃÂ±2M with an exposed binding site for the low density lipoprotein receptor, facilitating clearance of ÃÂ±2M-protease complexes from the body. This report establishes that protease activation also modulates a potent chaperone-like action of ÃÂ±2M which has broad specificity for proteins partly unfolded as a result of heat or oxidative stress. Protease-mediated activation of ÃÂ±2M abolishes its chaperone-like activity. However, native ÃÂ±2M is able to form soluble complexes with stressed proteins and then subsequently become activated by interacting with a protease, providing a potential mechanism for the in vivo clearance of ÃÂ±2M/stressed protein/ protease complexes. We propose that ÃÂ±2M is a newly discovered and unique member of a small group of abundant extracellular proteins with chaperone properties that patrol extracellular spaces for unfolded/misfolded proteins and facilitate their disposal.