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We performed in situ measurements of mechanical properties of individual W303 wild-type yeast cells by using an integrated environmental scanning electron microscope (ESEM) - nanomanipulator system. Compression experiments to penetrate a cell wall of an individual cell under two difference conditions, i.e. ESEM (600 Pa) and high vacuum (HV) (about 3 mPa) modes have been conducted. Data from the experiments clearly show a significant increase of about twenty five times of penetration force values from ESEM mode to HV mode; i.e. 152 nN and 4 muN for 5 mum cell size with sharp tip indenter. This can be further confirmed from quantitative estimation of average cell rigidity through the Hertz model, i.e. ESEM mode (2.16 plusmn 1.21 MPa) and HV (20.58 plusmn 2.09 MPa) for all cell sizes with sharp tip indenter. Further analysis also revealed that the size of the cells can influence its mechanical strength. As the size of the cell increases, the compression force needed to penetrate its wall also increases. From these experimental results, we can conclude that the force needed to penetrate a single cell does not only depend on the internal factor, i.e. cell size but also being influenced by the external factors, i.e. the environmental conditions.