Nonagglomerating polylactide (PLA) particles with various interaction forces were designed by covalent photografting. PLA particles were surface grafted with hydrophilic poly(acrylic acid) (PAA) or poly(acrylamide) (PAAm), and force interactions were determined using colloidal probe atomic force microscopy. Long-range repulsive interactions were detected in the hydrophilic/hydrophilic systems and in the hydrophobic/hydrophilic PLA/PLA-g-PAAm system. In contrast, attractive interactions were observed in the hydrophobic PLA/PLA and in the hydrophobic/hydrophilic PLA/PLA-g-PAA systems. AFM was also used in the tapping mode to determine the surface roughness of both neat and surface-grafted PLA film substrates. The imaging was performed in the dry state as well as in salt solutions of different concentrations. Differences in surface roughness were identified as conformational changes induced by the altered Debye screening length. To understand the origin of the repulsive force, the AFM force profiles were compared to the Derjaguin, Landau, Verwey, and Overbeek (DLVO) theory and the Alexander de Gennes (AdG) model. The steric repulsion provided by the different grafted hydrophilic polymers is a useful tool to inhibit agglomeration of polymeric particles. This is a key aspect in many applications of polymer particles, for example in drug delivery.