The design of effective crystallization inhibitors of calcium oxalate monohydrate (COM), the primary constituent of kidney stones, is a significant goal. Inhibitory molecules identified in urine include a small organic anion, citrate, and osteopontin (OPN), an aspartic acid-rich protein. The results of molecular-scale analyses combining force microscopy with molecular modeling raised the possibility that inhibition of COM crystallization might be increased by the additive effects of citrate and OPN because they act on different crystal faces. Constant composition (CC) kinetics studies of COM crystal growth now confirm that additive effects are, indeed, achieved in vitro when both citrate and OPN are present. These results suggest that a strategy employing combinations of inhibitors may provide a useful therapeutic approach to urinary stone disease. (c) 2006 Elsevier B.V. All rights reserved.