Background and Purpose— Ultrasound transiently expands perflutren-lipid microspheres (μS), transmitting energy momentum to surrounding fluids. We report a pilot safety/feasibility study of ultrasound-activated μS with systemic tissue plasminogen activator (tPA). Methods— Stroke subjects treated within 3 hours had abnormal Thrombolysis in Brain Ischemia (TIBI) residual flow grades 0 to 3 before tPA on transcranial Doppler (TCD). Randomization included Controls (tPA+TCD) or Target (tPA+TCD+2.8 mL μS). The primary safety end point was symptomatic intracranial hemorrhage (sICH) with worsening by ≥4 NIHSS points within 72 hours. Results— Fifteen subjects were randomized 3:1 to Target, n=12 or Control, n=3. After treatment, asymptomatic ICH occurred in 3 Target and 1 Control, and sICH was not seen in any study subject. μS reached MCA occlusions in all Target subjects at velocities higher than surrounding residual red blood cell flow: 39.8±11.3 vs 28.8±13.8 cm/s, P<0.001. In 75% of subjects, μS permeated to areas with no pretreatment residual flow, and in 83% residual flow velocity improved at a median of 30 minutes from start of μS infusion (range 30 s to 120 minutes) by a median of 17 cm/s (118% above pretreatment values). To provide perspective, current study recanalization rates were compared with the tPA control arm of the CLOTBUST trial: complete recanalization 50% versus 18%, partial 33% versus 33%, none 17% versus 49%, P =0.028. At 2 hours, sustained complete recanalization was 42% versus 13%, P =0.003, and NIHSS scores 0 to 3 were reached by 17% versus 8%, P =0.456. Conclusions— Perflutren μS reached and permeated beyond intracranial occlusions with no increase in sICH after systemic thrombolysis suggesting feasibility of further μS dose-escalation studies and development of drug delivery to tissues with compromised perfusion.