The selection of proteotypic peptides, that is, detectable unique representatives of proteins of interest, is a key step in targeted proteomics. To date, much effort has been made to understand the mechanisms underlying peptide detection in liquid chromatography-tandem mass spectrometry (LC-MS/MS) based shotgun proteomics and to predict proteotypic peptides in the absence of experimental LC-MS/MS data. However, the prediction accuracy of existing tools is still unsatisfactory. We find that one crucial reason is their neglect of the significant influence of protein proteolytic digestion on peptide detectability in shotgun proteomics. Here, we present an Advanced Proteotypic Peptide Predictor (AP3), which explicitly takes peptide digestibility into account for the prediction of proteotypic peptides. Specifically, peptide digestibility is first predicted for each peptide and then incorporated as a feature into the peptide detectability prediction model. Our results demonstrated that peptide digestibility is the most important feature for the accurate prediction of proteotypic peptides in our model. Compared with the existing available algorithms, AP3 showed 10.3-34.7% higher prediction accuracy. On a targeted proteomics data set, AP3 accurately predicted the proteotypic peptides for proteins of interest, showing great potential for assisting the design of targeted proteomics experiments.