We conducted a prospective open-labeled, clinical trial, with a two-by-two factorial design, of argon cold plasma (ACP) application and two different types of driveline positioning for the prevention of driveline infection (DLI) in patients with a left ventricular assist device (LVAD) implant. Here, we present the results of ACP application versus no ACP application. Eighty patients were allocated to the control group (no preventive ACP use; n = 40) or ACP group (preventive ACP use for 30 days post-LVAD implantation; n = 40). Patients were followed up for 1 year. The secondary endpoint was survival on device. Preventive ACP use improved 30 day freedom from DLI significantly (100% vs. 85%; p = 0.012); results remained significant at 6 months (92% vs. 69%, p = 0.007) and were 55% and 60%, respectively (p = 0.65) at 1 year follow-up. With respect to survival on device, results in the control and ACP groups did not differ significantly at 30 days (97.5% vs. 100%, respectively; p = 0.32), but tended to be lower in the control group than in the ACP group at 1 year follow-up (74% vs. 90%, respectively; p = 0.09). In conclusion, preventive ACP use was able to significantly reduce DLI both during the application period and up to 6 months after LVAD implantation.