Through the increased use of less expensive and counterfeit medicines, the contamination of parenteral fluids and drugs by particulate matter poses an increasing health hazard worldwide. However, the mechanism of action of such contamination has never been conclusively demonstrated. We have systemically injected the particles contained in three different 1-g preparations of the antibiotic cefotaxime into hamsters and visualized the functional capillary density in striated skin muscle, using intravital fluorescence microscopy. Injection of particles from either of the three preparations did not affect capillary perfusion in normal muscle (n = 3 hamsters, each). However, injection of particles from two generic drug preparations, but not the original preparation or the saline control, significantly reduced capillary perfusion in muscle tissue that had previously been exposed to 4 h of pressure-induced ischemia and 2 h of reperfusion (n = 9 hamsters per group). Histological sections demonstrated birefringent particles mechanically obliterating the microcirculation of the striated muscle. The loss of capillary perfusion due to particle injection or injection of standardized microspheres was dependent on the extent of ischemia/reperfusion-induced muscle injury, with more capillaries lost in the more severely compromised muscle areas. These findings suggest that particle contaminants may not pose a major threat in intact tissue, but may severely compromise tissue perfusion in patients with prior microvascular compromise of vital organs (i.e., after trauma, major surgery, or sepsis) and thus predispose to complications such as acute respiratory distress syndrome or multiple organ failure.