Cancer patients with long-term venous catheter are at risk for thromboembolic complications at the catheter tip and in the adjacent venous vessels. We assessed whether local thrombogenicity could be prevented with an experimental coated (with athrombogenic layer) catheter device (CD) compared to an uncoated CD. Patients requiring a long-term venous catheter were randomly allocated to receive either a standard uncoated or experimental coated (with athrombogenic Camouflage® layer) CD. The athrombogenic layer creates a barrier against non-specific adsorption of plasma proteins. The primary endpoint was urokinase injection in cases of an unsuccessful blood aspiration from the CD. Secondary endpoints included early (haematoma, pneumothorax) and late (venous thrombosis, infection) catheter-associated complications and catheter defects. One hundred and seventy-nine patients were randomly assigned to a CD (experimental n = 89/standard n = 90). One hundred and ten (62%) patients with a total of 1,286 catheter taps were analysed for the primary endpoint. Necessity for urokinase injection was 8/680 (1.2% experimental) vs. 33/606 (5.4% standard) per catheter tap and 4/55 (7.3% experimental) vs. 18/55 (32.7% standard) per patient. A repeated measures logistic regression to assess the effect of coating yielded an odds ratio of 3.5 (95% confidence interval, 1.2-10.4; p = 0.03) for the primary endpoint. All patients allocated per protocol were analysed for the secondary endpoints. Nine (5.4%) local thrombotic complications, seven (4.1%) catheter infections, and no catheter defect were observed. Athrombogenic coating of CD in cancer patients resulted in a significant reduced necessity for urokinase injections and subsequently less inconvenience for patients and fewer costly interventions.