Aspirin, an anti-inflammatory and anti-thrombotic drug, has become the focus of intense research as a potential anti-cancer agent owing to its ability to reduce tumor proliferation in vitro and to prevent tumorigenesis in patients. Studies have found an anti-cancer effect of aspirin when used in low, anti-platelet doses. However, the mechanism(s) through which low dose aspirin works is poorly understood. In this study we aimed to determine the effect of aspirin on the crosstalk between platelets and cancer cells. For our study we used 2 colon cancer cell lines isolated from the same donor but characterized by different metastatic potential, SW480 (nonmetastatic) and SW620 (metastatic) cancer cells, and a pancreatic cancer cell line, PANC-1 (nonmetastatic). We found that SW480 and PANC-1 cancer cell proliferation was potentiated by human platelets in manner dependent upon the upregulation and activation of the oncoprotein c-MYC. The ability of platelets to upregulate c-MYC and cancer cell proliferation was reversed by an anti-platelet concentration of aspirin. In conclusion, we show for the first time that inhibition of platelets by aspirin can affect their ability to induce cancer cell proliferation through the modulation of the c-MYC oncoprotein.