Mild hyperhomocysteinemia, a putative risk factor for arteriosclerotic outcomes, is seen in >85% of hemodialysis patients. Therapeutic strategies, including pharmacologic-dose B vitamin supplementation and "high-flux" or "super-flux" hemodialysis, have consistently failed to normalize total homocysteine (tHcy) levels in these patients. Predialysis plasma tHcy levels in 23 patients who were undergoing nocturnal hemodialysis (NHD) six or seven nights/wk were compared with those in 31 patients from the same Canadian dialysis unit who were undergoing chronic standard hemodialysis (SHD) (all <65 yr of age, undergoing thrice-weekly treatments). The SHD patients were similar to typical North American chronic hemodialysis patients with respect to B vitamin status and albumin, creatinine, and tHcy levels. Geometric mean tHcy levels for the NHD patients were significantly lower (12.7 versus 20.0 microM, P < 0.0001), as was the prevalence of mild-to-moderate hyperhomocysteinemia (>12 microM; NHD, 57%; SHD, 94%; P = 0.002). Analysis of covariance adjusted for plasma folate, vitamin B12, and pyridoxal 5'-phosphate levels, age, and gender confirmed that NHD was independently associated with 6.0 microM lower geometric mean tHcy levels (P = 0.001). It is concluded that tHcy levels are significantly lower among NHD patients, compared with SHD patients. Clinical trials will be necessary to confirm that NHD is effective in reducing tHcy levels among patients with dialysis-dependent end-stage renal disease.