Direct measurements of the depletion interaction between silica surfaces immersed in solutions of sodium poly(styrene sulfonate) have been made with the atomic force microscope, using the colloid probe technique. Significant variations in the interaction forces as a function of both the polymer molecular weight and the probe radius were observed. The depletion interaction yielded a secondary minimum in the observed force-distance profiles. This minimum was observed to increase in depth as a function of both the polymer molecular weight and the polymer concentration. The magnitude of the measured depletion interaction did not increase as much as expected when the size of the colloid probe was increased. The importance of surface asperities and local radii of curvature with respect to force measurements are discussed.