AbstractPurposeAn antibubble is an encapsulated gas bubble with an incompressible inclusion inside the gas phase. Current‐generation ultrasound contrast agents are bubble‐based: they contain encapsulated gas bubbles with no inclusions. The objective of this work is to determine the linear and nonlinear responses of an antibubble contrast agent in comparison to two bubble‐based ultrasound contrast agents, that is, reference bubbles and SonoVue.MethodsSide scatter and attenuation of the three contrast agents were measured, using single‐element ultrasound transducers, operating at 1.0, 2.25, and 3.5 MHz. The scatter measurements were performed at acoustic pressures of 200 and 300 kPa for 1.0 MHz, 300 kPa, and 450 kPa for 2.25 MHz, and 370 and 560 kPa for 3.5 MHz. Attenuation measurements were conducted at pressures of 13, 55, and 50 kPa for 1.0, 2.25, and 3.5 MHz, respectively. In addition, a dynamic contrast‐enhanced ultrasound measurement was performed, imaging the contrast agent flow through a vascular phantom with a commercial diagnostic linear array probe.ResultsAntibubbles generated equivalent or stronger harmonic signal, compared to bubble‐based ultrasound contrast agents. The second harmonic side‐scatter amplitude of the antibubble agent was up to 3 dB greater than that of reference bubble agent and up to 4 dB greater than that of SonoVue at the estimated concentration of bubbles/mL. For ultrasound with a center transmit frequency of 1.0 MHz, the attenuation coefficient of the antibubble agent was 8.7 dB/cm, whereas the attenuation coefficient of the reference agent was 7.7 and 0.3 dB/cm for SonoVue. At 2.25 MHz, the attenuation coefficients were 9.7, 3.0, and 0.6 dB/cm, respectively. For 3.5 MHz, they were 4.4, 1.8, and 1.0 dB/cm, respectively. A dynamic contrast‐enhanced ultrasound recording showed the nonlinear signal of the antibubble agent to be 31% greater than for reference bubbles and 23% lower than SonoVue at a high concentration of bubbles/mL.ConclusionEndoskeletal antibubbles generate comparable or greater higher harmonics than reference bubbles and SonoVue. As a result, antibubbles with liquid therapeutic agents inside the gas phase have high potential to become a traceable therapeutic agent.