Clinical criteria alone are insufficient to allow a diagnosis of intravascular catheter-related sepsis (CRS). A definite diagnosis of CRS usually requires removal of the catheter for quantitative catheter tip culture. However, only about 15-25% of central venous catheters (CVC) removed because infection is suspected actually prove to be infected, and the diagnosis is always retrospective. Other diagnostic tests, such as differential quantitative blood cultures from samples taken simultaneously from the catheter and a peripheral vein, have been proposed to avoid unjustified removal of the catheter and the potential risks associated with the placement of a new catheter at a new site: a central-to-peripheral blood culture colony count ratio of 5:1 to 10:1 is considered indicative of CRS. Despite its high specificity, the latter diagnostic technique is not routinely used in clinical practice because of its complexity and cost. The measurement of the differential time to positivity between hub blood (taken from the catheter port) and peripheral blood cultures might be a reliable tool facilitating the diagnosis of CRS in situ. In an in vitro study, we found a strong relationship between the inoculum size of various microorganisms and the time to positivity of cultures. When the times to positivity of cultures of blood taken simultaneously from central and peripheral veins in patients with and without CRS were examined, we found that earlier positivity of central vs peripheral vein blood cultures was highly correlated with CRS. Using a cut-off value of +120 min, the "differential time to positivity" of the paired blood samples, defined as time to positivity of the peripheral blood minus that of the hub blood culture, had 91% specificity and 94% sensitivity for the diagnosis of CRS. This method may be coupled with other techniques that have high negative predictive value, such as skin cultures at the catheter exit site. This diagnostic test can be proposed for routine clinical practice in most hospitals using automatic devices for blood cultures positivity detection. Endoluminal brushing of the catheter is considered sensitive and specific for the diagnosis of CRS, but the risk of embolisation or subsequent bacteraemia should be considered. Gram staining and the acridine-orange leucocyte cytospin test on through-catheter blood culture have been proposed for rapid diagnosis of CRS without catheter removal. The technique, which requires 100 microl catheter blood and the use of light and ultraviolet microscopy, is considered simple, rapid (30 min) and inexpensive. In conclusion, diagnostic tools such as paired blood cultures or Gram staining and the acridine-orange leucocyte cytospin test should allow a diagnosis of CRS without catheter removal in cancer patients.