Renal replacement therapy (RRT) may differentially affect systemic generation of reactive oxygen species and depletion of antioxidant pools of low molecular weight molecules and proteins. This study was designed to assess the magnitude of the impairment of serum total antioxidant capacity (TAC) in relation to different RRT modalities. The study included patients on continuous ambulatory peritoneal dialysis (CAPD, N = 21), hemodialysis (HD, N = 21), hemodiafiltration (HDF, N = 20), and healthy controls (N = 33). TAC was assessed by the ferric reducing ability of plasma (FRAP) and with the 2,2-diphenyl-1-picryl-hydrazyl (DPPH) assay. In CAPD patients, predialysis FRAP and DPPH were increased: 1.46 mM and 10.5% vs. control 1.19 mM and 7.2%, respectively (P < 0.001 in each). In HD and HDF patients, the FRAP and DPPH were significantly increased before and lowered after the RRT session (P < 0.05) if compared with healthy controls. During an HD session, FRAP was decreased from pre-HD 1.71 ± 0.29 mM to post-HD 0.85 ± 0.20 mM (P = 0.0001). The decrease of FRAP was lower during HDF (P < 0.05 vs. HD), it decreased from pre-HDF 1.41 ± 0.43 mM to post-HDF 0.87 ± 0.23 mM (P = 0.0001 vs. pre-HDF). The HD session decreased DPPH from the pre-HD median 10.3%, interquartile range (IR) 9.3–12.0% to post-HD 2.6% IR 2.3–3.1% (P < 0.0001). The adjustment of either urate or bilirubin up to pre-HD levels did not restore lowered post-HD levels of TAC. TAC remains preserved in CAPD, whereas the robust depletion of TAC, lower after HDF than HD sessions, cannot be attributed solely to the washout of dialyzable compounds.