Understanding mechanical properties of pharmaceutical solids at the submicron scale can be very important to pharmaceutical research & development. In this paper, the hardness of individual particles of various pharmaceutical solids including sucrose, lactose, ascorbic acid, and ibuprofen was quantified using the atomic force microscopy (AFM) nanoindentation. Effects of data variation and indentation size or peak load on hardness are evaluated. The results show acceptable reproducibility and indicate that data variation may be primarily from the inhomogeneous nature of the samples. Different extents of indentation size or peak load effect on hardness were observed for the samples. With consideration of both data variation and indentation size effects, the hardness values of different samples were compared at similar contact depths or peak loads. The hardness ranked as: ascorbic acid>sucrose>lactose approximately ibuprofen, at contact depths from approximately 40 to 400 nm or peak loads ranging from approximately 16 to 70 microN. Additionally, the potential implication of particle hardness to compact hardness and tableting performance was discussed.