Previous studies from the authors' laboratory have established the presence of estrogen and progesterone receptors in the human anterior cruciate ligament. The purpose of the current study was to investigate the combined effects of 1beta-estradiol and progesterone on cell proliferation and procollagen synthesis of the human anterior cruciate ligament fibroblasts. Fibroblast proliferation and procollagen synthesis in response to logarithmic concentrations of 17beta-estradiol (0.0025 ng/mL, 0.025 ng/mL, 0.25 ng/mL) and progesterone (1 ng/mL, 10 ng/mL, 100 ng/mL) were assessed with the measurement of 3H-thymidine incorporation and Types I and III procollagen specific equilibrium radioimmunoassays. On Days 1, 3, and 5 there was a dose dependent decrease in the fibroblast proliferation and procollagen Type I synthesis with increasing estradiol concentrations. The effect was attenuated with increasing progesterone concentrations. Controlling for estrogen levels, a dose dependent increase in fibroblast proliferation and procollagen Type I synthesis was observed with increasing progesterone concentrations. The effect was more pronounced at lower concentrations of estrogen, suggesting estrogen levels were the dominant factor. The effects of estrogen and progesterone became less apparent by Day 7. No significant differences in Type III procollagen synthesis were seen with varying estradiol concentrations at any of the designated times. These early physiologic changes in fibroblast proliferation and Type I procollagen synthesis may provide a biologic explanation for the increased anterior cruciate ligament injury rate observed in female athletes, suggesting the acute cyclical hormonal variations in the female athlete during menstruation predispose her to ligamentous injury.