Severe acute respiratory syndrome coronavirus type 2 (SARS‐CoV‐2) infection can lead to life‐threatening clinical manifestations. Patients with cardiovascular disease (CVD) are at higher risk for severe courses of COVID‐19. So far, however, there are hardly any strategies for predicting the course of SARS‐CoV‐2 infection in CVD patients at hospital admission. Thus, we investigated whether this prediction is achievable by prospectively analysing the blood immunophenotype of 94 nonvaccinated participants, including uninfected and acutely SARS‐CoV‐2‐infected CVD patients and healthy donors, using a 36‐colour spectral flow cytometry panel. Unsupervised data analysis revealed little differences between healthy donors and CVD patients, whereas the distribution of the cell populations changed dramatically in SARS‐CoV‐2‐infected CVD patients. The latter had more mature NK cells, activated monocyte subsets, central memory CD4+ T cells, and plasmablasts but fewer dendritic cells, CD16+ monocytes, innate lymphoid cells, and CD8+ T‐cell subsets. Moreover, we identified an immune signature characterised by CD161+ T cells, intermediate effector CD8+ T cells, and natural killer T (NKT) cells that is predictive for CVD patients with a severe course of COVID‐19. Thus, intensified immunophenotype analyses can help identify patients at risk of severe COVID‐19 at hospital admission, improving clinical outcomes through specific treatment.