Landscapes on either side of the martian topographic dichotomy bear distinct soil chemistry, but the processes associated with this distinction remain poorly understood. Here, correlation of soil chemistry at global to regional scales is examined with multivariate analysis of Gamma-Ray Spectrometer chemical maps and the Thermal Emission Spectrometer-derived Dust Cover Index (DCI). In the analysis, the northern lowlands show a strong S-Cl correlation, contrasting with the southern highlands, which show a stronger S-H 2 O correlation. These observations suggest aqueous interaction with soils throughout the southern highlands, preferentially dissolving Cl compounds and weakening S-Cl correlation. Strong S-Cl correlations in the northern lowlands suggest less interaction with aqueous H 2 O. Additionally, regional analyses demonstrate that DCI does not correlate with volatile chemistry at smaller scales and that Ca may be an important component of volatile-bearing material. These results provide new evidence for widespread aqueous interaction and possibly alteration of soil in the southern highlands.Plain Language Summary Mars can be divided into two large regions: the northern lowlands and southern highlands, separated by a planet-circling change in elevation known as the topographic dichotomy. The soils that cover the landscape in these two areas appear distinct from one another, although it is unclear what processes cause this distinction. This investigation examines the chemistry of soils on either side of the dichotomy based on Gamma-Ray Spectrometer data, to elucidate changes in soils. The identified changes in correlation of three soil components, sulfur, chlorine, and H 2 O, suggest that much of the southern highlands soils have interacted with water, but fluid interaction occurred far less in the northern lowlands. These findings show that the processes by which water interacts with soils were likely active over larger areas in the southern highlands than previously realized, but such processes were not active after the northern lowlands soils were deposited.