The pathogenesis of neuropathy and encephalopathy in patients with renal failure remains unknown. Possible factors include particularly aluminium intoxication, accumulation of certain middle molecular substances (MMS) and disturbances of tryptophan metabolism. Serum and CSF taken post-mortem from 8 uremic subjects who had been treated conservatively and from 4 patients on a chronic intermittent hemodialysis program who had dialysis dementia were subjected to MMS fractionation. Although MMS could not be detected in the CSF of normal controls, these substances were found in the CSF of uremic subjects in a pattern similar to that found in serum, although their concentrations were clearly lower than in serum. Their appearance could be due to impairment of the blood-CSF barrier. Uremic patients who had been treated conservatively had significantly increased CSF tryptophan concentrations when compared to the control subjects, but the CSF tryptophan concentrations of patients with dialysis dementia were in the normal range. Thus the pathogenesis of dialysis dementia cannot be related to the accumulation of MMS or to disturbances of tryptophan metabolism in the CSF.