ABSTRACT Background  Biocompatibility of haemodialysis membranes is the most important quality criteria to enable long‐term dialysis without major harmful effects. This study sought to evaluate the differences of genomic signatures derived from peripheral blood mononuclear cells (PBMC) in patients undergoing haemodialysis treatment using two different dialyser membranes: one semi‐synthetic and one full‐synthetic membrane. Design  Microarray experiments were conducted in PBMCs of four stable haemodialysis patients before and after dialysis comparing semi‐synthetic (Hemophan® GFS Plus 16) and full‐synthetic (Hemoflow® FX80) dialysis membranes, respectively. Genes differentially expressed when comparing the two different membranes used were analysed in order to elucidate the underlying molecular mechanisms affecting PBMCs in the course of dialysis treatment. Results  One hundred and seventy‐two genes were identified as up‐regulated after treatment with semi‐synthetic membranes when compared to full‐synthetic membranes. These genes could be assigned to processes including immunity and defence, signal transduction, and apoptosis. Dialysis with a full‐synthetic membrane, on the other hand, led to an activation of 72 genes that were mainly involved in cell cycle and cell cycle control. Conclusion  The over‐representation of genes belonging to immunity/defence, signal transduction, and apoptosis as found with semi‐synthetic membranes suggests that full‐synthetic membranes are more biocompatible than semi‐synthetic membranes.