Abstract Background A common complication of viral pulmonary infections, such as in the ongoing COVID-19 pandemic, is a phenomenon described as a “cytokine storm”. While poorly defined, this hyperinflammatory response results in diffuse alveolar damage. The low molecular weight fraction of commercial human serum albumin (LMWF5A), a novel biologic in development for osteoarthritis, demonstrates beneficial in vitro immunomodulatory effects complimentary to addressing inflammation, thus, we hypothesize that LMWF5A could improve the clinical outcomes of COVID-19 by attenuating hyperinflammation and the potential development of a cytokine storm. Presentation of the hypothesis A variety of human in vitro immune models indicate that LMWF5A reduces the production of pro-inflammatory cytokines implicated in cytokine storm associated with COVID-19. Furthermore, evidence suggests LMWF5A also promotes the production of mediators required for resolving inflammation and enhances the barrier function of endothelial cultures. Testing the hypothesis A randomized controlled trial, to evaluate the safety and efficacy of nebulized LMWF5A in adults with Acute Respiratory Distress Syndrome (ARDS) secondary to COVID-19 infection, was developed and is currently under review by the Food and Drug Administration. Implications of hypothesis If successful, this therapy may attenuate the cytokine storm observed in these patients and potentially reduce mortality, increase ventilation free days, improve oxygenation parameters and consequently lessen the burden on patients and the intensive care unit. Conclusions In conclusion, in vitro findings suggest that the immunomodulatory effects of LMWF5A make it a viable candidate for treating cytokine storm and restoring homeostasis to the immune response in COVID-19.