Background Individuals with sickle cell disease (SCD) are at risk for painful crises and long-term cardiopulmonary morbidity. Echocardiogram is recommended if signs or symptoms of cardiopulmonary disease develop in previously asymptomatic patients, or worsen in those with known disease. Second-generation echocardiogram contrast agents (ECAs) improve the diagnostic capacity of echocardiogram; however, these agents have risks in SCD populations that have yet to be investigated. Case summary We report a case series of two patients who experienced vaso-occlusive crises following administration of the ECA, Definity. Both patients were referred for echocardiogram from our institution’s sickle cell clinic because of concern for SCD-related cardiopulmonary complications. Both patients were in their usual state of health at the time of their exams. The first patient experienced acute back and hip pain minutes after receiving Definity and was diagnosed with acute vaso-occlusive crisis requiring admission for 6 days for pain management. The second patient developed dyspnoea and chest pain within 90 min of her echocardiogram. She was diagnosed with acute chest syndrome and admitted for further management. Her hospitalization was complicated by hyper-haemolysis and multiple organ failure syndrome. After 13 days, she was discharged home. Discussion The safety profile of ECAs has not been fully evaluated and warrants further study in individuals with SCD. Proposed mechanisms for our observations include the release of pro-inflammatory metabolites from Definity contrast agent’s shell and ultrasound-induced haemolysis secondary to ECA administration. Alternative imaging modalities and proper precautions should be considered when evaluating cardiopulmonary function in this patient population.