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Gold nanoparticles have been shown to enhance local radiation dose due to its high Z value.  Ultrasonically-stimulated microbubbles at therapeutic conditions can sensitize cells to ionizing radiation and enhance cell permeability allowing gold nanoparticles to cross the plasma membrane.  In this study, ultrasound-microbubble potentiated enhancement of cell death in combination with gold nanoparticles and ionizing radiation is investigated in vitro.  A suspension model of breast cancer (MDA-MB-231) cells was exposed to ultrasound and microbubbles (USMB), gold nanoparticles (AuNP) and ionizing radiation (XRT).  A 12 nm spherical AuNPs at concentrations of 7.8 x10¹⁰ nps/mL and 1.6 x 10¹¹ nps/mL were investigated at fixed USMB conditions of 500 kHz pulse center frequency, 580 kPa peak negative pressure, 10 μs pulse duration, 60s insonation time, Definity® microbubbles at 3.3% (v/v) and XRT dose of 2 Gy.  Cell viability post treatment was evaluated using clonogenic assay.  The application of AuNP and USMB induced a synergistic increase in cell death when combined with XRT.  A 22 fold increase in cell death was observed with the combined treatment (AuNP+USMB+XRT=3±0.4%) compared to radiotherapy only (XRT=65±3%).  The combined treatment of ultrasound-microbubbles with gold nanoparticles followed by radiotherapy induced a synergistic effect in cell death.