PURPOSE OF REVIEW: To discuss why severe COVID-19 should be considered sepsis and how co-infection and secondary infection can aggravate this condition and perpetuate organ dysfunction leading to high mortality rates. RECENT FINDINGS: In severe COVID-19, there is both direct viral toxicity and dysregulated host response to infection. Although both coinfection and/or secondary infection are present, the latest is of greater concern mainly in resource-poor settings. Patients with severe COVID-19 present a phenotype of multiorgan dysfunction that leads to death in an unacceptable high percentage of the patients, with wide variability around the world. Similarly to endemic sepsis, the mortality of COVID-19 critically ill patients is higher in low-income and middle-income countries as compared with high-income countries. Disparities, including hospital strain, resources limitations, higher incidence of healthcare-associated infections (HAI), and staffing issues could in part explain this variability. SUMMARY: The high mortality rates of critically ill patients with severe COVID-19 disease are not only related to the severity of patient disease but also to modifiable factors, such as the ICU strain, HAI incidence, and organizational aspects. Therefore, HAI prevention and the delivery of best evidence-based care for these patients to avoid additional damage is important. Quality improvement interventions might help in improving outcomes mainly in resource-limited settings.