Abstract Purpose We aimed to assess the effect of hemoglobin (Hb) concentration and oxygenation index on COVID-19 patients’ mortality risk. Patients and methods We retrospectively reviewed sociodemographic and clinical characteristics, laboratory findings, and clinical outcomes from patients admitted to a tertiary care hospital in Bogotá, Colombia. We assessed exploratory associations between oxygenation index and Hb concentration at admission and clinical outcomes. We used a generalized additive model (GAM) to evaluate the nonlinear relations observed and the classification and regression trees (CART) algorithm to assess the interaction effects found. Results From March to July 2020, 643 patients were admitted, of which 52% were male. The median age was 60 years old, and the most frequent comorbidity was hypertension (35.76%). The median value of SpO 2 /FiO 2 was 419, and the median Hb concentration was 14.8 g/dL. The mortality was 19.1% (123 patients). Age, sex, and history of hypertension were independently associated with mortality. We described a nonlinear relationship between SpO 2 /FiO 2 , Hb concentration and neutrophil-to-lymphocyte ratio with mortality and an interaction effect between SpO 2 /FiO 2 and Hb concentration. Patients with a similar oxygenation index had different mortality likelihoods based upon their Hb at admission. CART showed that patients with SpO 2 /FiO 2 < 324, who were older than 62 years, and had an Hb of ≥ 16 g/dl had the highest mortality risk (96%). Additionally, patients with SpO 2 /FiO 2 > 324 but Hb of < 12 and neutrophil-to-lymphocyte ratio of > 4 had a higher mortality likelihood (57%). In contrast, patients with SpO 2 /FiO 2 > 324 and Hb of > 12 g/dl had the lowest mortality risk (10%). Conclusion We found that a decreased SpO 2 /FiO 2 increased mortality risk. Extreme values of Hb, either low or high, showed an increase in likelihood of mortality. However, Hb concentration modified the SpO 2 /FiO 2 effect on mortality; the likelihood of death in patients with low SpO 2 /FiO 2 increased as Hb increased.