Many chemical reactions in Nature, the laboratory, and chemical industry occur in solvent mixtures that bring together species of dissimilar solubilities. Solvent mixtures are visually homogeneous, but are not randomly mixed at the molecular scale. In the all-important binary water-hydrotrope mixtures, small-angle neutron and dynamic light scattering experiments reveal the existence of short-lived (<50 ps), short-ranged (∼1 nm) concentration fluctuations. The presence of hydrophobic solutes stabilizes and extends such fluctuations into persistent, mesoscopic (10-100 nm) inhomogeneities. While the existence of inhomogeneities is well established, their impacts on reactivity are not fully understood. Here, we search for chemical signatures of inhomogeneities on the surfaces of W:X mixtures (W = water; X = acetonitrile, tetrahydrofuran, or 1,4-dioxane) by studying the reactions of Criegee intermediates (CIs) generated in situ from O3(g) addition to a hydrophobic olefin (OL) solute. Once formed, CIs isomerize to functionalized carboxylic acids (FC) or add water to produce α-hydroxy-hydroperoxides (HH), as detected by surface-specific, online pneumatic ionization mass spectrometry. Since only the formation of HH requires the presence of water, the dependence of the R = HH/FC ratio on water molar fraction expresses the accessibility of water to CIs on the surfaces of mixtures. The finding that R increases quasi-exponentially with in all solvent mixtures is consistent with CIs being preferentially produced (from their OL hydrophobic precursor) in X-rich, long-lived OL:X m W n interfacial clusters, rather than randomly dispersed on W:X surfaces. R vs dependences therefore reflect the average ⟨m, n⟩ composition of OL:X m W n interfacial clusters, as weighted by cluster reorganization dynamics. Water in large, rigid clusters could be less accessible to CIs than in smaller but more flexible clusters of lower water content. Since mesoscale inhomogeneities are intrinsic to most solvent mixtures, these phenomena should be quite general.