The structural features which make secretory IgA relatively resistant to proteolysis, compared to the major serum immunoglobulin IgG, were investigated. Secretory IgA, serum IgA, and IgG were incubated with pre-activated papain (4 hr) and Pronase (2 hr) at slightly alkaline pH in the absence of reducing agents. Digest mixtures were analyzed by Sephadex G-200 gel filtration and immunodiffusion. Under conditions which resulted in essentially quantitative cleavage of IgG1 myeloma proteins to Fab and Fc fragments, approximately 85% of secretory IgA, normal human serum IgA, and IgA myeloma proteins of both A1 and A2 subclasses remained undigested. Thus, both secretory IgA and serum IgA were relatively resistant to proteolysis compared to the major serum immunoglobulin, IgG1. Secretory IgA dimer was more resistant than IgA myeloma dimers since incubation with Pronase for 3 hr caused the depolymerization of the latter to a monomer-like fragment whereas secretory IgA dimer remained intact. Reduction with 10 mM dithiothreitol (DTT) and alkylation of serum IgA caused this immunoglobulin to become susceptible to proteolysis. Secretory IgA required a greater concentration of reducing agent (35 mM DTT) for conversion to the digestible form than did IgA myeloma dimers. Circular dichroism was used to detect conformational changes in both serum and secretory IgA which occurred after mild reduction and alkylation. Part of the conformation change in IgA proteins after mild reduction and alkylation was localized to the Fc fragment. It was concluded that secretory IgA was more resistant than the major serum immunoglobulin IgG1 and that this relative resistance was due in part to the greater resistance of immunoglobulin A per se, and in part due to additional stability of the secretory IgA form.