The biochemical hepatic iron index, defined as the ratio of hepatic iron concentration (expressed as micromoles per gram dry weight) to age permits accurate prediction of genetic status in patients with genetic hemochromatosis. However, the hepatic iron concentration is not always available. Therefore a histological hepatic iron index, defined as the ratio of total histological iron score (range = 0 to 60) to age, was evaluated in a total of 192 Australian and French patients with genetic hemochromatosis. These subjects had been classified previously as heterozygotes (n = 18) or homozygotes (n = 174) according to clinical and familial data only. Biochemical hepatic iron index and histological hepatic iron index were well correlated (Spearman's test: rho = 0.75, p <0.0001). Both were significantly (p <0.0001) increased in homozygotes (respectively, 6.7 +/- 3.8 [range = 1.2 to 22.6] and 0.62 +/- 0.28 [range = 0.14 to 1.5]) compared with heterozygotes (respectively, 1 +/- 0.4 [range = 0.45 to 1.6] and 0.08 +/- 0.05 [range = 0 to 0.14]). The histological hepatic iron index was less than 0.15 in all heterozygotes and greater than 0.15 in all but two homozygotes. These data show that the age-dependent nature of iron accumulation can also be accommodated by calculating the histological hepatic iron index and that histological study is an accurate means of predicting the genetic status of hemochromatosis patients when hepatic iron concentration is not available.