We seek to rapidly identify, test and develop combinations of repurposed drugs to enable cost-effective treatments that reduce the risk of disease or death from SARS-CoV-2 infection. We hypothesize that the morbidity and mortality of COVID-19 reflects overactive host inflammatory responses to infection and is not principally due to the primary direct cellular, organ and tissue damage attributable to viral infection. Stepwise clinical development has identified the combination of High Dose (HD) famotidine and celecoxib (famcox) as a promising adjuvant anti-inflammatory protocol. We now report results from a retrospective observational comparative cohort study designed to provide an estimate of the potential benefits, risks, prognosis and diagnostic laboratory findings associated with administration of dexamethasone in addition to famcox for treatment of newly hospitalized COVID-19 disease in a community hospital setting. Study enrollment was restricted to patients at WHO 4–5. In the group receiving adjuvant treatment with famcox without dexamethasone (active control) there were no deaths during hospitalization (0/18 = 0% mortality). A total of six deaths occurred in the group receiving famcox + dexamethasone (6/21 = 29% mortality). There was a significant difference in mortality between the two groups, Χ2 (1, N = 43) = 7.305, p < 0.007. Median time to event for reaching WHO score of < 4 was 3.5 days in the control group (famcox (–) dex) versus 10 days for the experimental group (famcox (+) dex) P < 0.001. We conclude that use of the potent non-specific anti-inflammatory corticosteroid dexamethasone in addition to the specific anti-inflammatory famcox protocol should only be considered in late stage COVID-19 disease in patients less than 70 years of age. The effects of added dexamethasone on laboratory biomarkers, and particularly on neutrophil count, lymphocyte count, and neutrophil to lymphocyte ratio raise concerns about the long-term effects of dexamethasone treatment with or without famcox during acute COVID-19 on the incidence and severity of chronic COVID (“long COVID” or PASC).