Abstract Background When blood passes the extracorporeal circuit, air microbubbles (MBs) contaminate the blood. Some MBs will end up as microemboli in the lung, heart, and brain. MB exposure has no medical purpose and is considered as bio-incompatibility. Selecting venous chambers with high removal rate of MBs is warranted to reduce the risks of air bio-incompatibility. The primary aim was to compare the Fresenius 5008 (F5008-VC) and the Emboless® (Emboless-VC) venous chambers regarding the elimination of MBs in the return bloodline during hemodialysis (HD). Methods Twenty patients underwent 80 sessions of cross-over HD using both the F5008-VC and the Emboless-VC randomized such that half started with the F5008-VC and half with the Emboless-VC. For 32 of the 80 sessions measurements were also performed during hemodiafiltrations (HDF) after the initial HD. MBs were measured with an ultrasound device (within the size range of 20-500µm) at the ‘Inlet’ and ‘Outlet’ bloodline of the venous chambers. The Wilcoxon pairwise test compared the percentage of MB elimination between venous chambers. Results During HD, the median reduction of MBs for the Outlet was 39% with the F5008-VC and 76% with the Emboless-VC (p<0.001). During HDF, the reduction was 28% with the F5008-VC and 70% with the Emboless-VC (p<0.001). Conclusion Fewer MBs and subsequently fewer microemboli entered the bloodline of the patient using the Emboless-VC compared to the F5008-VC venous chamber during HD and during HDF. Venous chambers with a high removal rate of MBs will reduce the extent of air emboli.