Although venesection therapy is well established for the initial depletion of iron stores in hereditary hemochromatosis, the frequency of subsequent therapy has not been clearly defined. In this study, 21 homozygotes (16 male, five female; mean age of 58, with a range of 26 to 77 years) who had completed initial venesection therapy were followed without further venesections for a mean of 4.0 years (range of 1 to 10.4 years) with iron reaccumulation assessed by annual serum ferritin concentration. Over the follow-up period, the mean rise in serum ferritin was 99 (micrograms/l)/year (range of 1.2 to 241 micrograms/l). The mean interval for the ferritin to become elevated above the normal range in 10 patients was 3.8 years. Eleven of 21 patients required no further venesection therapy over the follow-up interval. There was no significant correlation between the annual rate of ferritin increase and the age or amount of iron removed by prior venesections. These data demonstrate that monitoring body iron stores annually and the selective use of venesections if iron stores reaccumulate is a safe alternative to lifelong venesections every 2-4 months. Many homozygotes will not require reinitiation of venesection therapy for > 4 years. Annual monitoring of body iron stores with reinstitution of weekly venesection when the serum ferritin exceeds the upper limit of normal was a safe alternative to long-term maintenance venesection.