A family of naphthalenedisulfonate-binding antibodies catalyze the decarboxylation of 5-nitro-3-carboxybenzisoxazole, providing a series of structurally similar catalysts for investigating the influence of protein microenvironment on reactivity. Eight representative catalysts and one noncatalytic hapten binder have been characterized in detail to assess their catalytic properties. The Michaelis-Menten parameters, inhibition constants for hapten and product, and thermodynamic activation parameters are reported for each catalyst. The rate accelerations provided by the catalytic antibodies range from 1620 to 23 200. The antibodies display similar affinities for the hapten, substrate, and product, suggesting that binding differences are not the major cause of the variation in catalytic activity. Instead, catalytic efficiency appears to correlate roughly with-the hydrophobicity of the antibody active site as judged by fluorescence spectroscopy. Furthermore, five of the-catalytic antibodies fit an isokinetic relationship, displaying a wide variation in thermodynamic activation parameters characterized by enthalpy-entropy compensation. The data illustrate the potential of similar proteins to solve a specific chemical problem in slightly different ways and warrant detailed structural investigations to determine the precise combination of hydrogen bonding, electrostatic, and dispersive interactions that constitute medium effects in these related proteins.