COVID-19 critical illness has been associated with an abnormal fecal microbiota and dysregulated immune response. A healthy microbiome and its associated metabolome regulate the systemic immune system and may contribute to the course of COVID-19. Here we investigate whether an abnormal fecal microbiota and reduced metabolite production is associated with progressive COVID-19 respiratory failure and death. This prospective single-center observational study enrolled 102 patients with COVID-19 admitted to the intensive care unit with respiratory failure or shock. To examine the role of the microbiome early in the course of critical illness we limited the analysis to patients who provided a fecal specimen within 3 days of ICU admission (n= 71). Fecal samples underwent shotgun metagenomic DNA sequencing to define microbiome composition and metabolomic assays to determine microbiome function. A novel score, the Microbiome Health Index (MHI), was developed to integrate the composition and function of the microbiome into a single metric. The MHI includes alpha diversity, enterococcal domination (> 20% relative abundance), proteobacterial domination (> 5% relative abundance) in addition to levels of secondary bile acids and short chain fatty acids. Points are given for lack of diversity, domination with pathogenic bacteria, low levels of secondary bile acids and low levels of short chain fatty acids in comparison to values in healthy donor feces. Baseline demographics, clinical features, and microbiome composition and function were included in a univariable analyses for mortality and progression of respiratory failure requiring intubation. Multivariable models included all clinical variables with P-value< 0.3 on univariable analysis. The MHI was the sole variable included as an assessment of microbiome health. Greater microbiome dysfunction, as assessed by the MHI score, was independently associated with mortality (HR= 1.19, CI= 1.02-1.39, p= 0.025)(Table 1). In patients receiving high flow nasal cannula at the time of ICU admission (n= 52), greater microbiome dysfunction, assessed with the MHI, was independently associated with progression of respiratory failure, defined as receipt of invasive mechanical ventilation or death (RR= 1.04, CI= 1.01-1.08, p= 0.024). Microbiome dysfunction quantified by the MHI, a novel assessment of composition and function, was associated with mortality in patients with COVID-19 associated critical illness. In patients receiving HFNC at ICU admission, the MHI score was also independently associated with progression of respiratory failure. Next steps include untangling the mechanism behind this association and the development of therapeutics to support a healthy microbiota.