Abstract Purified human haptoglobins have been subjected to reductive cleavage by β-mercaptoethanol in 8 M urea or 6 M guanidine. The reduction of haptoglobin 1-1 and 2-2 exposes 18 and 24 SH groups/mole of protein, respectively. Removal of denaturing reagents and reactivation in the presence of O 2 and a catalytic amount of thiol was followed by the regain of the chemical and immunological properties of the native protein. Under the most favorable conditions of reoxidation the yield of haptoglobin, estimated by molecular size and hemoglobin binding capacity, ranged between 60 and 90%. Reactivation was also obtained when equimolecular mixtures of isolated and separately reactivated α and β chains were incubated at pH 8.15 and 20°. The formation of a stable complex between β-haptoglobin and an hemoglobin dimer (αβ) did not interfere with the reassociation of the former with the α 1 haptoglobin chain. The refolding process is highly specific and occurs (although with a lower yield of protein) also when haptoglobins are reduced and reoxidized together with other proteins containing SH groups.