Collagen-induced activation of platelets in suspension leads to ␣ IIb ␤ 3 -mediated outside-in signaling, granule release, thromboxane A2 (TxA2) production, and aggregation. Although much is known about collagen-induced platelet signaling, the roles of TxA2 production, adenosine diphosphate (ADP) and dense-granule secretion, and ␣ IIb ␤ 3 -mediated outside-in signaling in this process are unclear. Here, we demonstrate that TxA2 and ADP are required for collagen-induced platelet activation in response to a low, but not a high, level of collagen and that ␣ IIb ␤ 3 -mediated outside-in signaling is required, at least in part, for this TxA2 production and ADP secretion.