Austria started its COVID-19-vaccination program in December 2020 with three different vaccines. As the vaccination program continues, we encountered increased 2-[18F] FDG-activity not only in axillary lymph nodes ipsilateral to the injection site but also in other organs. The aim of this retrospective study is to present results of the metabolic activity of ipsilateral axillary lymph nodes, liver, blood pool, spleen, and bone marrow after three different vaccines. To our knowledge, this is the first study to examine systemic response changes in relation to time after COVID-19 vaccination using three different vaccines. The collected data of 220 eligible vaccinated patients (127 with BioNTech/Pfizer BNT162b2, 61 with Moderna, and 32 with AstraZeneca) examined with 2-[18F] FDG-PET/CT were enrolled. The PET/CT examinations were evaluated from day 1 to day 135 (SD: 23.2, median: 26) after different vaccinations. Seventy-one out of these 220 patients underwent a pre-vaccination 2-[18F] FDG -PET/CT. SUVmax of axillary node(s), and blood pool, liver, spleen, and bone marrow as reference organs were calculated. The ratio of SUVmax activity of axillary lymph node to reference organs was also compared in all patients. The tracer activity dynamics were investigated in three different vaccines. After BioNTech/Pfizer vaccination 2-[18F] FDG activity in axillary lymph nodes shows a steady decrease in all patients. Ten days after vaccination the 2-[18F] FDG uptake was at its highest activity. Seventy days after vaccination, tracer activity is not different from the background activity of 2-[18F] FDG in the axillary region. This result also applies to other two vaccines; however, in the 4th week after Moderna vaccination SUVmax in lymph nodes showed the highest peak of tracer activity. With AstraZeneca the highest activity was at the earlier days. There was no significant statistical difference of SUVmax of lymph nodes or its ratios to other reference organs between three groups of vaccines. SUVmax in lymph nodes was statistically significant lower than SUVmax in the liver, spleen, and bone marrow with p-values of < 0.001, 0.044, and 0.001, respectively. In the group of 71 patients with a pre-vaccination PET/CT examination, the median SUVmax of lymph nodes increased significantly after vaccination from 0.82 (IQR 0.59-1.38) to 1.80 (IQR 1.07-3.89)(p < 0.001). In contrast median tracer activity in the liver decreased from 3.37 (IQR 2.83-3.91) to 3.11 (2.56-3.70) (p = 0.032). There was no significant change of tracer activity after vaccination in other reference regions (mediastinum, spleen, and bone marrow). In this group of 71 patients, there was also no significant difference in tracer activity in different types of vaccines. Local site and ipsilateral axillary lymph node activity in 2-[18F] FDG PET/CT after COVID19-vaccination is suggested in many studies. The main challenge is recognizing the changes in lymph nodes during time after vaccination to minimize false interpretation, foremost in patients with oncological diagnoses. Moreover, different vaccines cause different system metabolic changes. The knowledge of vaccine type, the time interval between vaccination and PET/CT scan is essential, especially in therapy evaluation.© 2023. The Author(s).