We examine an ensemble of 48 simulated clusters to determine the effects of small-scale density fluctuations and large-scale substructure on X-ray measurements of the intracluster medium (ICM) mass. We measure RMS density fluctuations in the ICM which can be characterized by a mean mass-weighted clumping factor C = <rho^2>/<rho>^2 between 1.3 and 1.4 within a density contrast of 500 times the critical density. These fluctuations arise from the cluster history of accretion shocks and major mergers, and their presence enhances the clusters luminosity relative to the smooth case. We expect, therefore, that ICM mass measurements utilizing models which assume uniform density at a given radius carry a bias of order sqrt(C) = 1.16. We verify this result by performing ICM mass measurements on X-ray images of the simulations and finding the expected level of bias. The varied cluster morphologies in our ensemble also allow us to investigate the effects of departures from spherical symmetry on our measurements. We find that the presence of large-scale substructure does not further bias the resulting gas mass unless it is pronounced enough to produce a second peak in the image of at least 1% the maximum surface brightness. We analyze the subset of images with no secondary peaks and find a bias of 9% and a Gaussian random error of 4% in the derived mass.
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