Human intervention studies have suggested an exciting synergistic action between calcium supplementation and aspirin intake in reducing the risk of colorectal cancer. The aim of this study was to determine whether such a synergy can be demonstrated on azoxymethane (AOM)-induced colon aberrant crypt foci (ACF) formation in mice and rats. Female CF-1 mice and male F344 rats were injected subcutaneously with AOM and then received diet treatments for 8 wk. The basal control diet contained high fat (20% mixed lipids by weight) and low calcium (1.4 mg/g diet) to mimic the average Western diet. The treatment diets contained enriched calcium (5.2 mg calcium/g diet), aspirin (0.2 mg aspirin/g diet), or calcium plus aspirin (5.2 mg calcium plus 0.2 mg aspirin/g diet). Treatment with calcium, aspirin, or their combination significantly decreased the number of total ACF and aberrant crypt per mouse (by 43-59%) or rat (by 23-38%), but statistically significant differences among the 3 groups were not observed. A hint of additivity between calcium and aspirin was observed in mice but not in rats. These results indicate that the combination of calcium and aspirin did not produce a synergistic effect on the ACF formation in AOM-treated mice and rats.