Sixty-five regular hemodialysis patients, maintained on stable dialysis schedules for at least one month, were investigated to assess the relationship between uremic morbidity and the accumulation of individual middle molecule fractions (MM). Pre-dialysis plasma levels of MM were determined by the use of gel chromatography followed by ion exchange gradient elution chromatography. Thirty-three symptom-free patients were compared with 32 patients who exhibited uremic symptoms or complications (overhydration, the depletion syndrome, chronic or recurrent infection, isolated episodes of infection and pericarditis). The plasma concentrations of urea and creatinine were no higher in the symptomatic groups than in the controls. On the other hand, all the symptomatic groups showed higher levels of fraction 7 c in plasma than the controls. In addition, overhydration and chronic or recurrent infection were associated with high plasma levels of 7 f and 7 b respectively. Six patients with depletion syndrome, three of whom had progressive peripheral neuropathy, had significantly elevated plasma concentrations of MM including not only fraction 7 c but also fractions 7 b and 7 d. At the time of acute infections, plasma levels of 7 c were considerably higher than when the same patients were free from symptoms. Despite the association between uremic morbidity and the accumulation of MM, there is a great overlap between asymptomatic controls and "sick" uremic patients with regard to plasma levels of MM.