Drug seizures containing carfentanil continue to increase in Palm Beach County, FL, USA despite international efforts to control the distribution of the drug. The analysis of drug seizures from the county in 2016 and 2017 demonstrated that carfentanil was the most commonly identified fentanyl analog and was most often detected in combination with heroin, fentanyl, furanyl fentanyl and/or other fentanyl analogs. Carfentanil is an ultra-potent opioid requiring a method with adequate sensitivity for detection in blood specimens from impairment cases. Previous research indicated that carfentanil could not be identified in biological specimens by routine drug testing protocols and that detection requires targeted analysis with greater sensitivity. Due to the prevalence of carfentanil in drug seizures, a sensitive targeted qualitative method by liquid chromatography tandem mass spectrometry in antemortem blood samples was evaluated, validated and implemented. The method included identification of carfentanil, acetyl fentanyl, beta-hydroxythiofentanyl, butyryl fentanyl, fentanyl, furanyl fentanyl, kavain, mitragynine, MT-45 and U-47700. In 2017 carfentanil was the second most frequently detected drug, after ethanol, in driving under the influence blood cases. Of all blood cases in which drug testing was performed (n = 145), carfentanil was detected in 38% followed by alprazolam (29%), fentanyl (27%), delta-9-tetrahydrocannabinol (24%) and morphine (23%). In toxicology cases carfentanil was rarely identified alone (only four cases) and was most commonly identified with other opioids (73% of cases), benzodiazepines (43%) and stimulants (29%). The high incidence of carfentanil-positive cases detected by this method underscores the importance of continually monitoring regional drug seizure trends, and evaluating the adequacy of toxicology testing panels based on these trends.