This study aims to address a significant challenge in understanding the devastating tissue damage caused by SARS-CoV-2, which leads to multi-organ failure due to cytokine release syndrome. Traditional models using human tissue organoids have advanced the understanding of SARS-CoV-2 infection mechanisms, but lack crucial components such as immune and endothelial cells. The study introduces vascular immune organoids (VIOs) created from human pluripotent stem cells to include these missing components. When examining the effect of SARS-CoV-2 infection on these organoids, the study found that infections activated inflammatory macrophages. Additionally, the upregulation of interferon signaling demonstrated the macrophages’ role in cytokine release syndrome. These vascular immune organoids provide a useful platform to model and identify factors that could mitigate the effects of SARS-CoV-2-induced cytokine release syndrome.