Purpose The National Institute for Occupational Safety and Health (NIOSH) released a proposed protocol in 2015 to evaluate the vapor containment abilities of closed system transfer device technologies in order to provide meaningful comparisons between products. This study assessed the vapor containment ability of closed system transfer devices when following the methodology as outlined by the 2015 NIOSH proposed protocol. Methods This study evaluated six closed system transfer device brands following the draft NIOSH vapor containment protocol. The testing evaluated each closed system transfer device brand during both compounding (Task 1) and administration (Task 2). Five pre-specified steps for each task were repeated for a total of four manipulations per device. The Thermo Scientific™ MIRAN SapphIRe XL Infrared Analyzer was used to detect isopropyl alcohol vapor levels after each step. Results For Task 1, two closed system transfer device products (PhaSeal™ and Equashield®) adequately contained the isopropyl alcohol vapor and passed the predefined testing criteria. The same two products, plus one additional product (ChemoLock™), contained the vapor for Task 2 manipulations. Based on the results of this study, only two out of the six closed system transfer device brands passed testing criteria for both tasks, functioning as truly closed systems. Conclusion To improve employee safety in chemotherapy preparation, closed system transfer devices that demonstrate no leakage should be the preferred choices of healthcare systems. In this study, PhaSeal™ and Equashield® proved to be adequately closed in both Task 1 and Task 2, while ChemoLock™ proved to be closed in Task 2 but not in Task 1. All other products failed both tasks when measuring for isopropyl alcohol vapor release.