We studied the long-term changes in hematocrit in 283 center hemodialysis patients. Mean duration of dialysis (+/- SD) was 53.8 +/- 43.4 months, with a range of 6 to 176 months. The correlations of hematocrit with clinical factors, laboratory values, and renal cystic changes were investigated. Time on dialysis was the strongest single predictor of hematocrit for the whole group (r = 0.351, P less than 0.001) and for men and women analyzed separately. Longitudinal 5-year (n = 83) and 10-year (n = 21) data showed a continuous increase in hematocrit levels over time (r = 0.414, P less than 0.001 over 10 years). Patients at the dialyzer reuse center (n = 224) had higher hematocrit levels than those at the center that did not reuse (n = 59). Although time on dialysis was strongly correlated with increasing extent of renal cystic change (r = 0.387, P less than 0.001), the correlations of cyst extent and time on dialysis with hematocrit were not independent by multiple regression analysis. We conclude that hematocrit increases progressively over time in patients on chronic hemodialysis. The mechanisms responsible for this do not seem to involve cystic transformation of the kidneys and remain unclear.