Platelets contribute to the development of metastasis, the most common cause of mortality in cancer patients, but the precise role that anti‐platelet drugs play in cancer treatment is not defined. Metastatic tumor cells can produce platelet αIIbβ3 activators, such as ADP and thromboxane A₂ (TXA₂). Inhibitors of platelet β3 integrins decrease bone metastases in mice but are associated with significant bleeding. We examined the role of a novel soluble apyrase/ADPase, APT102, and an inhibitor of TXA₂ synthesis, acetylsalicylic acid (aspirin or ASA), in mouse models of experimental bone metastases. We found that treatment with ASA and APT102 in combination (ASA + APT102), but not either drug alone, significantly decreased breast cancer and melanoma bone metastases in mice with fewer bleeding complications than observed with αIIbβ3 inhibition. ASA + APT102 diminished tumor cell induced platelet aggregation but did not directly alter tumor cell viability. Notably, APT102 + ASA treatment did not affect initial tumor cell distribution and similar results were observed in β3−/− mice. These results show that treatment with ASA + APT102 decreases bone metastases without significant bleeding complications. Anti‐platelet drugs such as ASA + APT102 could be valuable experimental tools for studying the role of platelet activation in metastasis as well as a therapeutic option for the prevention of bone metastases. J. Cell. Biochem. 104: 1311–1323, 2008. © 2008 Wiley‐Liss, Inc.