Background Quantum dots (QDs) have numerous possible applications for in vivo imaging. However, toxicity data are scarce. Objectives To determine the acute in vivo toxicity of QDs with carboxyl surface coating (carboxyl-QDs) and QDs with amine surface coating (amine-QDs), we investigated the inflammatory properties, tissue distribution, and prothrombotic effects after intravenous injection. Methods We performed particle characterization by transmission electron microscopy and dynamic light scattering. Carboxyl-QDs and amine-QDs were intravenously injected in mice (1.44–3,600 pmol/mouse). At different time intervals, analyses included fluorescence microscopy, blood cell analysis, bronchoalveolar lavage, wet and dry organ weights, and cadmium concentration in various organs. We examined the prothrombotic effects in vivo by assessing the effect of pretreatment with the anticoagulant heparin and by measuring platelet activation (P-selectin), and in vitro by platelet aggregation in murine and human platelet-rich plasma exposed to QDs (1.44–1,620 pmol/mL). Results At doses of 3,600 and 720 pmol/mouse, QDs caused marked vascular thrombosis in the pulmonary circulation, especially with carboxyl-QDs. We saw an effect of surface charge for all the parameters tested. QDs were mainly found in lung, liver, and blood. Thrombotic complications were abolished, and P-selectin was not affected by pretreatment of the animals with heparin. In vitro, carboxyl-QDs and amine-QDs enhanced adenosine-5′-diphosphate–induced platelet aggregation. Conclusion At high doses, QDs caused pulmonary vascular thrombosis, most likely by activating the coagulation cascade via contact activation. Our study highlights the need for careful safety evaluation of QDs before their use in human applications. Furthermore, it is clear that surface charge is an important parameter in nanotoxicity.