Quantitative strategies relying on stable isotope labeling and isotope dilution mass spectrometry have proven a very robust alternative to the well established gel-based techniques for the study of the dynamic proteome. Post-digestion 18O labeling is becoming very popular mainly due to the simplicity of the enzyme-catalyzed exchange reaction, the peptide handling and storage procedures, and the flexibility and versatility introduced by decoupling protein digestion from peptide labeling. Despite recent progresses, peptide quantification by post-digestion 18O labeling still involves several computational problems. In this work we analyze the behavior of large collections of peptides when they are subjected to post digestion labeling and conclude that it can be explained by a universal kinetic model. On the basis of this observation, we have developed an advanced quantification algorithm for this kind of labeling. Our method fits the entire isotopic envelope to parameters related with the kinetic exchange model, allowing at the same time an accurate calculation of the relative proportion of peptides in the original samples and of the specific labeling efficiency of each one of the peptides. We demonstrate that the new method eliminates artifacts produced by incomplete oxygen exchange in subsets of peptides that have a relatively low labeling efficiency, and that may be considered indicative of false protein ratio deviations. Finally, using a rigorous statistical analysis based on the calculation of error rates associated with false expression changes, we show the validity of the method in the practice by detecting significant expression changes, produced by the activation of a model preparation of T-cells, with only 5 g of protein, in three proteins among a pool of more than one hundred. By allowing a full control over potential artifacts, our method may contribute to improve automation of the procedures for relative protein quantification using this labeling strategy.