We conducted the present study with the hypothesis that conflicting reports on the association between mild hypothyroidism and breast cancer may be due to failure to consider the potential interaction between thyroid and ovarian hormones. Seventy-three cases of breast cancer and 75 hospital controls were studied. The overall matched multivariate odds ratio of breast cancer for the lowest tertile of free T4 (< or = 1.10 ng/dl) versus the two other tertiles was 1.7 (95% confidence limits, 0.6-5.0). However, there was a statistically significant linear trend (P = 0.04) in the odds ratios for breast cancer related to subnormal free T4 levels across tertiles of duration of ovulatory activity. These results suggest that women combining low levels of circulating free T4 with long duration of ovulatory activity may be at increased risk for this disease.