The ability to distinguish harmful solid cerebral emboli from gas bubbles intra-operatively has potential to direct interventions to reduce the risk of brain injury. In this in vitro study, two embolus discrimination techniques, dual-frequency (DF) and frequency modulation (FM) methods, are simultaneously compared to assess discrimination of potentially harmful large pieces of carotid plaque debris (0.5–1.55 mm) and thrombus-mimicking material (0.5–2 mm) from gas bubbles (0.01–2.5 mm). Detection of plaque and thrombus-mimic using the DF technique yielded disappointing results, with four out of five particles being misclassified (sensitivity: 18%; specificity: 89%). Although the FM method offered improved sensitivity, a higher number of false positives were observed (sensitivity: 72%; specificity: 50%). Optimum differentiation was achieved using the difference between peak embolus/blood ratio and mean embolus/blood ratio (sensitivity: 77%; specificity: 81%). We conclude that existing DF and FM techniques are unable to confidently distinguish large solid emboli from small gas bubbles (<50 μm).