The objective of the study was to evaluate the effectiveness of chlorhexidine-impregnated sponges for reducing catheter-related infections of central venous catheters inserted for cancer chemotherapy. The method used was a randomized, prospective, open, controlled clinical study (three-step group sequential analysis protocol). The patients were from two high dependency units at a university hospital undergoing chemotherapy for haematological or oncological malignancies requiring central venous catheters (CVCs) expected to remain in place for at least 5 days. Six hundred and one patients with 9,731 catheterization days were studied between January 2004 and January 2006. Patients admitted for chemotherapy received chlorhexidine and silver sulfadiazine-impregnated triple-lumen CVCs under standardized conditions and were randomized to the groups receiving a chlorhexidine gluconate-impregnated wound dressing or a standard sterile dressing. Daily routine included clinical assessment of the insertion site (swelling, pain, redness), temperature, white blood count and C-reactive protein. Catheters remained in place until they were no longer needed or when a CVC-related infection was suspected. Infection was confirmed with blood cultures via the catheter lumina and peripheral blood cultures according to the time-to-positivity method. Six hundred and one patients were included. The groups were comparable with respect to demographic and clinical data. The incidence of CVC-related infections were 11.3% (34 of 301) and 6.3% (19 of 300) in the control and chlorhexidine-impregnated wound dressing groups, respectively (p=0.016, relative risk 0.54; confidence interval 0.31-0.94). Especially, catheter-related infections at internal jugular vein insertions could be reduced (p=0.018). No adverse effects related to the intervention were observed. The use of chlorhexidine-impregnated wound dressings significantly reduced the incidence of CVC-related infections in patients receiving chemotherapy.