Epidemiological and pathological data suggest that thyroid cancer may well be an estrogen-dependent disease. The relationship between thyroid cancer risk and dietary phytoestrogens, which can have both estrogenic and antiestrogenic properties, has not been previously studied. We present data from a multiethnic population-based case-control study of thyroid cancer conducted in the San Francisco Bay Area. Of 817 cases diagnosed between 1995 and 1998 (1992 and 1998 for Asian women), 608 (74%) were interviewed. Of 793 controls identified through random-digit dialing, 558 (70%) were interviewed. Phytoestrogen consumption was assessed via a food-frequency questionnaire and a newly developed nutrient database. The consumption of traditional and nontraditional soy-based foods and alfalfa sprouts were associated with reduced risk of thyroid cancer. Consumption of "western" foods with added soy flour or soy protein did not affect risk. Of the seven specific phytoestrogenic compounds examined, the isoflavones, daidzein and genistein [odds ratio (OR), 0.70; 95% confidence interval (CI), 0.44-1.1; and OR, 0.65, 95% CI, 0.41-1.0, for the highest versus lowest quintile of daidzein and genistein, respectively] and the lignan, secoisolariciresinol (OR, 0.56; 95% CI, 0.35-0.89, for the highest versus lowest quintile) were most strongly associated with risk reduction. Findings were similar for white and Asian women and for pre- and postmenopausal women. Our findings suggest that thyroid cancer prevention via dietary modification of soy and/or phytoestrogen intake in other forms may be possible but warrants further research at this time.