Heme oxygenase 1 expression is increased in pediatric patients with malaria. The carboxyhemoglobin level (a measure of heme oxygenase 1 activity) has not been assessed in adult patients with malaria. Results of pulse co-oximetry revealed that the mean carboxyhemoglobin level was elevated in 29 Indonesian adults with severe falciparum malaria (10%; 95% confidence interval [CI], 8%–13%) and in 20 with severe sepsis (8%; 95% CI, 5%–12%), compared with the mean levels in 32 patients with moderately severe malaria (7%; 95% CI, 5%–8%) and 36 controls (3.6%; 95% CI, 3%–5%; P < .001). An increased carboxyhemoglobin level was associated with an increased odds of death among patients with severe malaria (odds ratio, 1.2 per percentage point increase; 95% CI, 1.02–1.5). While also associated with severity and fatality, methemoglobin was only modestly increased in patients with severe malaria. Increased carboxyhemoglobin levels during severe malaria and sepsis may exacerbate organ dysfunction by reducing oxygen carriage and cautions against the use of adjunctive CO therapy, which was proposed on the basis of mouse models.