COVID-19 caused substantial damage for the world and more than one million individuals succumbed to this contagious disease. During the 2020-2021 autumn-winter season, there was a huge wave of new COVID-19 infection cases in the United States (US). We intend to investigate whether this high COVID-19 burden had a link to adverse drug reactions in the US, thus we extracted online data from the US Food and Drug Administration (FDA) comparing the adverse drug effect-related mortality between two autumn-winter seasons (2020/2021 cohort 1 vs 2022/2023 cohort 2). The primary outcome is measured via multi-variable logistic regression models which adjust age, sex, and drug indication. A second analysis investigated the association between the high COVID-19 burden and the adverse drug effect mortality for the 25 most reported drugs during the two seasons. The average age is 58.87 vs 59.27 years, respectively. In Cohort 1 54.29% are females and in Cohort 2 the percentage is 55.32%. The crude mortality in Cohort 1 is 19.80% and in Cohort 2 it is 20.72%. We did not find a positively significant primary outcome and the odd ratio (OR) of high COVID-19 burden for adverse drug effect mortality is 0.946 (95%CI 0.926-0.965, p < .0001). However, the subgroup analysis shows for some drugs, most of which compromise the immune response, the high COVID-19 burden is linked to increased risk of death significantly. They include adalimumab, clozapine, duplilumab, lendlidomide, palbocicib, pomalidomide, rivaroxaban, tofacitib, ibrutinib, and updadacit. Our study probably provides preliminary evidence supposing that patients suffering an adverse drug effect involving the immune system from medications might be at increased risk for deteriorating outcomes during the high pandemic burden period of a serious and contagious disease. However, future prospective studies are needed to confirm the results. We think an adverse drug reaction mitigation strategy during future pandemics is needed to better protect those who take these drugs.