In crowded solutions the presence of many cosolutes often affects the stability of compact polymers, such as globular proteins. Important examples of crowded environments are those inside some cells, where protein stability or aggregation rates are affected by the presence of coexisting bio-macromolecules. In the present article the concept of depletion force from colloidal physics and theoretical techniques developed for polymer science have been applied to study the effects of macromolecular crowding on protein stability. A continuous three-dimensional polymer model is used to simulate the behavior of protein under the conditions of macromolecular crowding and the depletion force based on such a model is calculated. Calculated results have been compared with the measured results in our laboratory, where the enhancement of the forces required to unfold ubiquitin molecules in a solution crowded with dextran has been measured using single-molecule atomic force microscopy techniques. Comparison between the calculated results and experimental observations shows that only qualitative agreement has been reached in the sense that both show a larger force required because of crowding as a protein molecule is mechanical stretched, but the magnitude of the enhancement of the unfolding force theoretically predicted is small compared to the measured value. Possible sources of discrepancy and improvements of the model are discussed. (c) 2006 Elsevier Ltd. All rights reserved.