There is now a large amount of evidence indicating that women with extensive areas of mammographic densities are 4-6 times more likely to develop breast cancer than those with little or no density in the mammogram. We have examined one potential biological explanation for this association by estimating the incidence of various histological types of benign breast disease in relation to mammographic density. We studied the large cohort of women taking part in the National Breast Screening Study (NBSS), a randomized trial of screening with mammography. Mammograms from subjects with biopsies (n = 423) and from a comparison group of subjects randomly selected from the NBSS (n = 465) were included. Histological slides from biopsied subjects (n = 353) were classified independently by the pathologists of the NBSS and by a review pathologist (H.M.J.). Mammographic density in more than 75% of the breast area was associated with an increased risk of incidence of hyperplasia without atypia, and of atypical hyperplasia and/or carcinoma in situ. The classifications of the review pathologist showed that, compared to women with no density, the relative risk of incident lesions for women with density in more than 75% of breast was 13.85 (95% CI 2.65-72.49) for hyperplasia, and 9.23 (95% CI 1.66-51.48) for atypical hyperplasia and/or carcinoma in situ. These findings suggest that the association between extensive mammographic density and breast cancer risk may, at least in part, be attributable to biological processes in the breast that give rise to these histological features that are known to be related to breast cancer risk.