Differences in the relative molar response observed for a series of closely related analytes in glycerol solution using secondary ion mass spectrometry are attributable largely to differences in surface activity. These differences can be minimized if a relatively large quantity of a surfactant of opposite charge is added to the solution before analysis. This added surfactant is chosen to dominate the surface selectively with the result that differences in surface activity among the species of interest become unimportant. The added surfactant does not interfere because its complementary charge state ensures very low response relative to the species of interest. It is further demonstrated that, in much the same way, surfactants can be used to enhance the response of an analyte relative to a matrix such as glycerol. This paper describes the first reported application of surfactants as reagents to modify the secondary ion mass spectra of liquid solutions.