Titratable residues determine the acid/base behavior of proteins, strongly influencing their function; in addition, proton binding is a valuable reporter on electrostatic interactions. We describe a method for pKa calculations, using constant-pH Monte Carlo (MC) simulations to explore the space of sidechain conformations and protonation states, with an efficient and accurate generalized Born model (GB) for the solvent effects. To overcome the many-body dependency of the GB model, we use a “Native Environment” approximation, whose accuracy is shown to be good. It allows the precalculation and storage of interactions between all sidechain pairs, a strategy borrowed from computational protein design, which makes the MC simulations themselves very fast. The method is tested for 12 proteins and 167 titratable sidechains. It gives an rms error of 1.1 pH units, similar to the trivial “Null” model. The only adjustable parameter is the protein dielectric constant. The best accuracy is achieved for values between 4 and 8, a range that is physically plausible for a protein interior. For sidechains with large pKa shifts, ≥2, the rms error is 1.6, compared to 2.5 with the Null model and 1.5 with the empirical PROPKA method. © 2013 Wiley Periodicals, Inc.