High-intensity focused ultrasound was used to insonify simulated vitreous hemorrhages in two in vitro models and one in vivo animal model. Histopathologic evaluation of the treatment effect was performed with light and electron microscopy. Ultrasonic parameters resulting in histopathologically proven disruption and hemolysis of intravitreal blood were investigated. Most important in obtaining this effect were the temporal average acoustic power and pulse repetition rate of the applied ultrasonic beam. Accurate positioning of the therapeutic beam and visualization of internal spatio-temporal response patterns in the blood during insonification were monitored via simultaneous diagnostic B-mode imaging. Results suggested that high-intensity focused ultrasound might facilitate the two major mechanisms involved in the natural resorption process of vitreous hemorrhages namely hemolysis and surface-dependent phagocytosis.