CONTEXT: Estrogen has been suggested as a risk factor for thyroid cancer. OBJECTIVE: The aim of this study is to examine the associations between hysterectomy, bilateral salpingo-oophorectomy (BSO), and incidence of thyroid cancer. DESIGN: This was a prospective cohort study. SETTING: The study was conducted at 40 clinical centers in the United States. PARTICIPANTS: A total of 127 566 women aged 50-79 were enrolled in the Women's Health Initiative during 1993-1998. MAIN OUTCOME MEASURES: Hysterectomy and BSO were self-reported. Incident thyroid cancer cases were confirmed by medical record review. RESULTS: Three hundred forty-four incident thyroid cancer cases were identified during an average of 14.4 years of follow-up. Compared with women without hysterectomy, women with hysterectomy, regardless of ovarian status, had a significantly higher risk of thyroid cancer (hazard ratio 1.46 [95% confidence interval 1.16-1.85]). Hysterectomy with BSO was not associated with a lower risk for thyroid cancer compared with hysterectomy alone. Among women with hysterectomy alone, hormone therapy use was associated with lower risk of thyroid cancer (hazard ratio 0.47 [95% confidence interval 0.28-0.78]). However, we did not observe significant associations between hormone therapy use and thyroid cancer in women without hysterectomy or women with hysterectomy plus BSO. CONCLUSION: Our large prospective study observed that hysterectomy, regardless of oophorectomy status, was associated with increased risk of thyroid cancer among postmenopausal women. In addition, our data did not support the hypotheses that exogenous estrogen is a risk factor or that estrogen deprivation is a protective factor for thyroid cancer. Further research is needed to clarify whether these apparent associations may be due to shared risk factors between indications for hysterectomy and thyroid cancer.