PURPOSE: Although many studies have linked obesity with increased risk of thyroid cancer, few have investigated the role of obesity-related lifestyle characteristics and medical conditions in the etiology of this disease. We examined the associations of self-reported physical activity and diabetes history with thyroid cancer risk in a large pooled analysis of prospective cohort studies. METHODS: Data from five prospective studies in the U.S. (n = 362,342 men, 312,149 women) were coded using standardized exposure, covariate, and outcome definitions. Hazard ratios (HR) and 95% confidence intervals (CI) for thyroid cancer were estimated using age as the time metric and adjusting for sex, education, race, marital status, cigarette smoking, body mass index, alcohol intake, and cohort. Effect modification by other risk factors (e.g., age, sex, and body mass index) and differences by cancer subtype (e.g., papillary, follicular) were also examined. RESULTS: Over follow-up (median = 10.5 years), 308 men and 510 women were diagnosed with a first primary thyroid cancer. Overall, subjects reporting the greatest amount of physical activity had an increased risk of the disease (HR = 1.18, 95% CI:1.00-1.39); however, this association was restricted to participants who were overweight/obese (≥25 kg/m(2); HR = 1.34, 95% CI:1.09-1.64) as opposed to normal-weight (<25 kg/m(2); HR = 0.92, 95% CI:0.69-1.22; P-interaction = 0.03). We found no overall association between self-reported history of diabetes and thyroid cancer risk (HR = 1.08, 95% CI:0.83-1.40). CONCLUSION: Neither physical inactivity nor diabetes history was associated with increased risk of thyroid cancer. While it may have been a chance finding, the possible increased risk associated with greater physical activity warrants further investigation.