As the techniques to connect percutaneous coronary intervention (PCI) balloons and the inflation syringe vary in the instructions for use and in practice, we measured the amount of air in PCI balloons after testing three connection methods to an inflation syringe. Following the preparation using one of the three methods, 114 balloons and stent balloons were tested four times. Method 1 connected the syringe and the balloon catheter directly after purging and filling the lumen, while method 3 omitted the purging and filling process. With method 2, the catheter lumen was purged, filled and fully vented via a three-way valve. The primary endpoint answered whether air remained in the balloon, and if so, the secondary endpoint indicated the total volume of remaining air. The connection with a three-way valve achieved significantly less air in the inflated balloon as compared with either direct connection approach (27% vs. 44% and 51%; p = 0.015). For the direct connection, no significant difference between purging and filling the lumen prior to making the connection or not existed. According to these findings, the best method to connect a PCI balloon to the inflation syringe while removing air involves using a three-way valve.