Background: Many cancer patients receive a central venous catheter or port system prior to therapy to assure correct drug administration. Even appropriate hygienic intervention maintenance carries the risk of contaminating the middle port (C-port) of a three-way cock (TWC), a risk that increases with the number of medical interventions. Because of the complexity of the cleaning procedure with disconnection and reconnection of the standard luer lock cap (referred as "intervention"), we compared luer lock caps with a "closed access system" consisting of a luer access split septum system with regard to process optimization (work simplification, process time), efficiency (costs) and hygiene (patient safety). Methods: For determination of process optimization the workflow of an intervention according to the usual practice and risks was depicted in a process diagram. For determining the actual process costs, we analyzed use of material and time parameters per intervention and used the process parameters for programming the process into a simulation run (n = 1000) to determine the process costs as well as their differences (ACTUAL vs. NOMINAL) within the framework of a discrete event simulation. Additionally cultures were carried out at the TWC C-ports to evaluate possible contamination. Results: With the closed access system, the mean working time of 5.5 minutes could be reduced to 2.97 minutes. The results for average process costs (labour and material costs per use) were 3.92 (sic) for luer lock caps and 2.55 (sic) for the closed access system. The hypothesis test (2-sample t-test, CI 0.95, p-value<0.05) confirmed the significance of the result. In 50 reviewed samples (TWC's), the contamination rate for the luer lock cap was 8% (4 out of 50 samples were positive), the contamination rate of the 50 samples with the closed access system was 0%. Possible hygienic risks (related to material, surroundings, staff handling) could be reduced by 65.38%. Conclusions: In the present research, the closed access system with a divided split septum was superior to conventional luer lock caps. The advantage of the closed access system lies in the simplified handling for staff, which results in a reduced risk of patient infection due to improved clinical hygiene.