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All natural surfaces exhibit nanoscale roughness (NR) and chemical heterogeneity (CH) to some extent. Expressions were developed to determine the mean interaction energy between a colloid and a solid–water interface, as well as for colloid–colloid interactions, when both surfaces contain binary NR and CH. The influence of heterogeneity type, roughness parameters, solution ionic strength (IS), mean zeta potential, and colloid size on predicted interaction energy profiles was then investigated. The role of CH was enhanced on smooth surfaces with larger amounts of CH, especially for smaller colloids and higher IS. However, predicted interaction energy profiles were mainly dominated by NR, which tended to lower the energy barrier height and the magnitudes of both the secondary and primary minima, especially when the roughness fraction was small. This dramatically increased the relative importance of …