Two independent investigations of catalysis by BSA and other serum albumins are combined to provide detailed insight into the mechanism of a classical proton-transfer reaction taking place on the surface of a protein. The Kemp, elimination involves the general base-catalyzed removal of a proton from carbon and is known to be highly sensitive to medium effects. The serum albumins bind and catalyze the eliminative fragmentation of 5-nitrobenzisoxazole, with remarkable efficiency and "accidental specificity:" A binding site and a likely catalytic lysine are identified, and factors contributing to the efficiency of catalysis analyzed. A key factor appears to be a differentiated microenvironment, which allows delocalized negative charge to develop in a stabilizing hydrophobic pocket next to a polar region where the developing ammonium cation is not disfavored. Catalytic efficiency is discussed in terms of effective molarities fur the reaction catalyzed by serum albumins and by catalytic antibodies and compared with a selection of published EMs for enzyme-catalyzed reactions.