For the purification of biopharmaceutical proteins, liquid chromatography is still the gold standard. Especially with increasing product titers, drawbacks like slow volumetric throughput and high resin costs lead to an intensifying need for alternative technologies. Selective preparative protein precipitation is one promising alternative technique. Although the capability has been proven, there has been no precipitation process realized for large-scale monoclonal antibody (mAb) production yet. One reason might be that the mechanism behind protein phase behavior is not completely understood and the precipitation process development is still empirical. Mechanistic modeling can be a means for faster, material-saving process development and a better process understanding at the same time. In preparative chromatography, mechanistic modeling was successfully shown for a variety of applications. Lately, a new isotherm for hydrophobic interaction chromatography (HIC) under consideration of water molecules as participants was proposed, enabling an accurate description of HIC. In this work, based on similarities between protein precipitation and HIC, a new precipitation model was derived. ... mehrIn the proposed model, the formation of protein–protein interfaces is thought to be driven by hydrophobic effects, involving a reorganization of the well-ordered water structure on the hydrophobic surfaces of the protein–protein complex. To demonstrate model capability, high-throughput precipitation experiments with pure or prior to the experiments purified proteins lysozyme, myoglobin, bovine serum albumin, and one mAb were conducted at various pH values. Polyethylene glycol (PEG) 6000 was used as precipitant. The precipitant concentration as well as the initial protein concentration was varied systematically. For all investigated proteins, the initial protein concentrations were varied between 1.5 mg/mL and 12 mg/mL. The calibrated models were successfully validated with experimental data. This mechanistic description of protein precipitation process offers mathematical explanation of the precipitation behavior of proteins at PEG concentration, protein concentration, protein size, and pH.