Carbon monoxide (CO) poisoning is a prevalent global cause of death. This is the first epidemiological study investigating the relationship between CO poisoning (silent killer) and the cause of death in autopsy forensic samples received from 2009 to 2020 at the Poison Control and Forensic Medical Chemistry Center, Jeddah, Saudi Arabia. MethodsThe cause of death was classified based on the carboxyhemoglobin saturation level (COHb) in the postmortem blood samples. In 170 post-mortem cases, the level of COHb was positive. The double-wavelength spectrophotometric method was used to quantify the COHb and the samples were confirmed by another spectrophotometer techniques AVOXmeter 4000 system. ResultsJust more than half (58%) of the deaths were due to CO intoxication, and the median level of the COHb in the postmortem blood samples was 56%. The study confirmed that the cause of the death in 15% of the sample were classified as CO-related intoxication (median COHb 21%), and 27% had no relation with CO intoxication or undetermined cause of death (COHb level ≤ 10%). The manner of death was classified as accidental, suicidal, homicidal, natural or unknown cause of death. The majority (72%) of the causes of death was accidental death, 10% due to suicide, 4% to homicide and 5% to natural death with no relationship to CO poisoning. The manner of deaths were unknown in 15 cases due to a lack of information. ConclusionAlthough CO poisoning globally appears to decline, the rate in Jeddah remained stable through the study period. Safety and preventive educational interventions are required to reduce CO poisoning.