To compare the drugs observed in homicides in two cities in the American Mid-West. We looked at drugs detected in two major American cities in the Mid-West in 2020 to determine which drugs were most commonly associated with homicides in recent years. All cases that were reported as homicides (by whatever means) in 2020 in Cook County (Chicago, Illinois) and Wayne County (Detroit, Michigan) were included. For purpose of this study, only common drugs of abuse were included since frequently comprehensive toxicology testing is not performed in homicide cases. Only drugs with a reported incidence of > 1.0% were included. Toxicology testing for drugs consisted of immunoassay screening followed confirmation testing by either LC-MS/MS or GC-MS. Ethanol was screened using dual-column headspace GC-FID with confirmation by single column headspace GC-FID on a second aliquot. For the 986 homicide cases (rate = 19K/100K) in Cook County the most common drugs were cannabinoids (60%), ethanol (28%), methylenedioxymethamphetamine (MDMA, 12%), cocaine (benzoylecgonine 7.7%, cocaine, 4.8%, cocaethylene 2.0%), fentanyl (6.8%), methamphetamine (5.1%), morphine (3.2%), midazolam (2.3%), phencyclidine (2.3%), alprazolam (1.7%), oxycodone (1.4%), 6-acetylmrophine (1.4%) and methadone (1.2%). For the 441 homicide cases (rate = 25K/100K) in Wayne County the most common drugs were cannabinoids (52%), ethanol (29%), cocaine (benzoylecgonine 9.1%, cocaine 5.7%, cocaethylene 2.0%), fentanyl (8.8%), oxycodone (7.2%), methamphetamine (5.0%), morphine (4.8%), midazolam (2.3%), 6-acetylmorphine (1.8%), alprazolam and hydrocodone (1.6% each), and lorazepam and nordiazepam (1.4%, each). A review of the results demonstrated some similarities as well as some distinct differences between the Cook and Wayne County cohorts. Notably, the most common stimulant drug observed in Cook County homicides cases was MDMA ( n = 122) compared to only a single observation in Wayne County homicides. Other stimulant drugs – cocaine and methamphetamine – were similar in both counties. Historically CNS depressants were less commonly observed in homicides than stimulants, but with the ubiquitous abuse of fentanyl it was not surprising to see a considerable number of homicide cases positive for that drug. The hallucinogen, Phencyclidine, was also observed in 23 Cook County homicides and with no observations in Wayne County. It has been noted that the use of a stimulant drug with ethanol can cause behavioral effects of both the stimulant drug and the disinhibitive effects of ethanol leading to behavior that may put the individual at greater risk for homicide. Stimulants combined with ethanol were detected in 101 (10%) of Cook County homicides, but only 16 (3.6%) of Wayne County homicides. Multiple stimulant drugs were detected in 30 Cook County and 6 Wayne County homicides. While the homicide rate in Cook County was lower than in Wayne County, the number of homicides was more than double, possibly associated with the greater use of stimulant drugs. Drugs of abuse are frequently associated with homicide cases, but the drugs may vary regionally. Notably in the Chicago the presence of MDMA and PCP was frequently observed while this was not the case in Detroit. Historically, cocaine was observed in around 30% of homicides in urban areas. While cocaine is still frequently associated with homicides, other stimulant drugs such as methamphetamine and, regionally, MDMA and PCP are now often detected.