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There is a lack of studies aiming to assess cellular a disintegrin and metalloproteinase-17 (ADAM-17) activity in COVID-19 patients and the eventual associations with the shedding of membrane-bound angiotensin-converting enzyme 2 (mACE2). In addition, studies that investigate the relationship between ACE2 and ADAM-17 gene expressions in organs infected by SARS-CoV-2 are lacking. We used data from the Massachusetts general hospital COVID-19 study (306 COVID-19 patients and 78 symptomatic controls) to investigate the association between plasma levels of 33 different ADAM-17 substrates and COVID-19 severity and mortality. As a surrogate of cellular ADAM-17 activity, an ADAM-17 substrate score was calculated. The associations between soluble ACE2 (sACE2) and the ADAM-17 substrate score, renin, key inflammatory markers, and lung injury markers were investigated. Furthermore, we used data from the Genotype-Tissue Expression (GTEx) database to evaluate <i>ADAM-17</i> and <i>ACE2</i> gene expressions by age and sex in ages between 20–80 years. We found that increased ADAM-17 activity, as estimated by the ADAM-17 substrates score, was associated with COVID-19 severity (<i>p</i> = 0.001). ADAM-17 activity was also associated with increased mortality but did not reach statistical significance (<i>p</i> = 0.06). Soluble ACE2 showed the strongest positive correlation with the ADAM-17 substrate score, follow by renin, interleukin-6, and lung injury biomarkers. The ratio of <i>ADAM-17</i> to <i>ACE2</i> gene expression was highest in the lung. This study indicates that increased ADAM-17 activity is associated with severe COVID-19. Our findings also indicate that there may a bidirectional relationship between membrane-bound ACE2 shedding via increased ADAM-17 activity, dysregulated renin–angiotensin system (RAS) and immune signaling. Additionally, differences in <i>ACE2</i> and <i>ADAM-17</i> gene expressions between different tissues may be of importance in explaining why the lung is the organ most severely affected by COVID-19, but this requires further evaluation in prospective studies.