Cyanide is produced by die combustion of natural and synthetic materials. It is assumed that cyanide poisoning is a major component of smoke inhalation injury; however, scientific verification of this assumption is lacking. In this study we examined blood carboxyhemoglobin and cyanide levels in fire fatalities. Carboxyhemoglobin levels of 433 fatalities averaged 44.9% and exceeded fatal (≥50%) levels in 195 cases. Cyanide levels of 364 fatalities averaged 1.0 mg/L and exceeded fatal levels (>3 mg/L) in 31 cases. For victims with cyanide levels above 3 mg/L the mean carboxyhemoglobin level was 62.5%. Cyanide poisoning is infrequent in fire fatalities, and when present it is associated with significant carboxyhemoglobinemia. Cyanide can be both produced and degraded in blood and tissue, making interpretation of blood levels difficult. In survivors of fire, detoxification of cyanide can occur without specific antidotes with the use of aggressive supportive care. Specific assay and treatment for cyanide poisoning is rarely necessary in the treatment of victims of smoke and fire.