Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global health emergency, in which its effective treatment and prevention remain obscured. Hyperpyrexia is an elevation of body temperature above 106.7 degrees F (41.5 degrees C) due to an abnormally increased hypothalamic-thermoregulatory set. The pathophysiology, impact, and outcomes of hyperpyrexia in patients with COVID-19 have not yet been studied. Herein, we present clinical features and outcomes of six patients with COVID-19 who had developed hyperpyrexia during hospitalization. All patients expired shortly after the onset of hyperpyrexia. Hyperpyrexia seems to adversely impact the outcomes and mortality in patients with COVID-19. The underlying mechanisms of developing hyperpyrexia in COVID-19 are mysterious. We propose it may be caused by SARS-CoV-2-related brain injury, exuberant immune response, and thrombus formation. More research is needed to verify our results. Understanding the association between hyperpyrexia and SARS-CoV-2 will help to elucidate the COVID-19 pathogenesis, which is mandatory for developing effective treatment strategies.