Background and Objectives: An association between high red blood cell distribution width (RDW) and mortality has been found in several diseases, including infection and sepsis. Some studies have aimed at determining the association of elevated RDW with adverse prognosis in COVID-19, but its usefulness has not been well established. The objective of this study was to determine the accuracy of the RDW, measured at hospital admission and discharge, for predicting death in patients with COVID-19. Materials andMethods: An observational, retrospective, longitudinal, and analytical study was conducted in two different COVID-19 reference centers in the state of Guanajuato, Mexico. A total of 323 patients hospitalized by COVID-19 were included. Results: We found higher RDW levels at the time of hospital admission in the non-survivors group compared to levels in survivors (median = 13.6 vs. 13.0, p < 0.001). Final RDW levels were even higher in the deceased group when compared with those of survivors (median = 14.6 [IQR, 12.67–15.6] vs. 12.9 [IQR, 12.2–13.5], p < 0.001). For patients who died, an RDW > 14.5% was more common at the time of death than for patients who survived at the time of discharge (81 vs. 13 patients, p < 0.001; RR = 2.3, 95% CI 1.89–2.81). Conclusions: The RDW is an accessible and economical parameter that, together with other characteristics of the presentation and evolution of patients with COVID-19, can be helpful in determining the prognosis. An RDW that increases during hospitalization could be a more important mortality predictor than the RDW at hospital admission.