Vancomycin and piperacillin/tazobactam are known to be incompatible. The objectives of the present study were to evaluate the impact of their simultaneous infusion on mass flow rates and particulate load and identify preventive strategies. We assessed both static conditions and a reproduction of an infusion line used in a hospital’s critical care unit. A high-performance liquid chromatography/UV diode array system and static and dynamic laser diffraction particle counters were used. The mass flow rates were primarily influenced by the choice of the infusion device and the presence of simulated fluid volume support. Drug incompatibility also appeared to affect vancomycin’s mass flow rate, and the dynamic particulate load increased during flow rate changes - especially in the infusion set with a large common volume line and no concomitant simulated fluid volume support. Only discontinuation of the piperacillin/tazobactam infusion was associated with a higher particulate load in the infusion set with a large common volume line and no concomitant simulated fluid volume support. A low common volume line and the use of simulated fluid volume support were associated with smaller fluctuations in the mass flow rate. The clinical risk associated with a higher particulate load must now be assessed.