Abstract Background T-cell responses are a crucial constituent in the adaptive immunity to SARS-CoV-2 and can be quantified using interferon-gamma (IFN-γ) release assays (IGRAs). This study aimed at comparing the results of two commercial IGRA systems, the EUROIMMUN Quan-T-Cell SARS-CoV-2 and the Oxford Immunotec T-SPOT.COVID, presenting the first head-to-head comparison of these two assays for the evaluation of SARS-CoV-2-specific T-cell activity. Methods Blood samples were collected at the Public Health Institute Ostrava from 90 health care professionals with a history of COVID-19 infection or vaccination. All samples were tested for T-cell-mediated immunity using the two IGRAs as well as for humoral immunity using the EUROIMMUN Anti-SARS-CoV-2 QuantiVac ELISA IgG and an in-house virus neutralization test. Results Similar results were obtained by both IGRAs, yet the sensitivity of the Quan-T-Cell appeared to be insignificantly higher than that of the T-SPOT.COVID. Conclusion Both assays demonstrated excellent overall agreement with virus neutralization activity and anti-S IgG positivity, with the only exception that 4/6 subjects in the subgroup of unvaccinated Omicron convalescents were devoid of IgG. In these cases, however, T-cell responses were at least borderline positive, indicating that IGRAs provide higher sensitivity in detecting immune responses to SARS-CoV-2 than do IgG-specific assays. This applies particularly to unvaccinated persons who contracted only SARS-CoV-2 Omicron variant infection but is also likely to be relevant to other patient groups.