Patients with end-stage renal disease display enhanced genomic damage that may have pathophysiologic relevance for cancer development and cardiovascular complications. We investigated to what extent the genomic damage in peripheral blood lymphocytes can be modulated #1: by initiation of standard hemodialysis (SHD) in formerly conservatively treated end-stage renal disease patients, #2: by a switch from SHD to hemodiafiltration, and #3: daily dialysis (DHD). Genomic damage was evaluated by the micronuclei (MN) frequency test and the comet assay (CA). In a prospective study we found that initiation of SHD did not induce significant changes of genomic damage in peripheral blood lymphocytes whereas the change to hemodiafiltration improved the percentage of DNA in the tail as measured by CA without modulating the MN frequency. In a cross-sectional investigation the degree of genomic damage as evaluated by MN frequency was significantly lower in a patient group treated by DHD as compared with a group treated by SHD. In the DHD patients there also was a significant decrease of the plasma concentrations of urea and the advanced glycation end products imidazolone A, carboxymethyllysine, and of advanced glycation end product-associated fluorescence.