Radioactive iodine is in widespread use for the treatment of hyperthyroidism. Data on long-term safety outcome are limited and conflicting. The objectives of this study were to evaluate the association of radioiodine treatment for hyperthyroidism with overall cancer and with specific cancer types.This is a historical cohort study, using the Clalit healthcare database. Participants were all adults with a new diagnosis of hyperthyroidism in 2002 to 2015, newly treated with radioactive iodine, or with thionamides (propylthiouracil/thiamazole), excluding patients with previous malignancies. Age, sex, smoking history, body mass index, Clalit district, socioeconomic status, history of diabetes mellitus and of hypertension, use of aspirin and of statins, and adherence to cancer screening procedures were used to calculate propensity-score to receive radioiodine. Incidence rates and 95% confidence intervals were calculated for overall cancer occurrence, and for each cancer type using Poisson distribution. Association between study variables and time to cancer event was evaluated using cause-specific hazard ratios (HR) and 95% confidence intervals (CI), estimated by univariate and propensity-score adjusted multivariable Cox proportional hazards models. For sensitivity analysis we stratified the cohort by calendar year at cohort entry and by length of follow-up.16,637 patients formed the study cohort, with 123,166 person-years of follow-up. There was no association between radioiodine treatment and increased risk of overall cancer HR=0.99 (0.83-1.19, p=0.91), HR= 1.01 (0.83-1.21, p=0.95) (univariate and multivariable analyses, respectively). However, in a sensitivity analysis, we found an association with overall cancer risk in the first period of follow-up (up to 4.2 years) HR 2.11 (1.59-2.80) (p<0.0001), and no association with increased risk in a longer follow-up period. An association was found between radioiodine exposure and an increased risk for non-Hodgkin's lymphoma (NHL), in univariate but a non-significant increased risk in multivariable analysis: HR 2.89 (1.12-7.46,p=0.03), HR 2.32 (0.88-6.13,p=0.09), respectively.No association was found between radioiodine treatment for hyperthyroidism and risk for incident cancer in long-term follow-up. In an analysis of specific cancer types, a statistically significant association was found with NHL only in univariate analysis.