In January 2014, the US government temporarily designated 5F-PB-22, along with three other synthetic cannabinoids (AB-FUBINACA, ADB-PINACA and PB-22), into Schedule I. Over the course of a 4-month time period (July-October 2013), our laboratory quantitatively identified 5F-PB-22 in specimens obtained from four postmortem cases. We describe the four cases, to include pertinent autopsy findings and decedent histories, together with quantitative results for 5F-PB-22 determined in postmortem blood and antemortem serum. Samples were prepared via a liquid-liquid extraction at pH 10.2 into hexane : ethyl acetate. Instrumental analysis was achieved with liquid chromatography coupled with electrospray ionization tandem mass spectrometry operating in multiple reaction monitoring mode. Two ion transitions were monitored for the analyte of interest, and one ion transition was monitored for the internal standard. The observed concentration range of 5F-PB-22 is 1.1-1.5 ng/mL for three postmortem blood specimens and one antemortem serum specimen. Three of the decedents experienced abrupt, sudden death; however, one decedent expired after a rapidly deteriorating hospital course.