BACKGROUND: A systematic overview and meta-analysis of studies reporting data on hypothyroidism (HT) after radiation therapy was conducted to identify risk factors for development of HT. METHODS: Published studies were identified from the PubMed and Embase databases and by hand-searching published reviews. Studies allowing the extraction of odds ratios (OR) for HT in 1 or more of several candidate clinical risk groups were included. A meta-analysis of the OR for development of HT with or without each of the candidate risk factors was performed. Furthermore, studies allowing the extraction of radiation dose-response data were identified for a meta-analysis of the dose-response curve. RESULTS: Female gender (OR = 1.6; 95% confidence interval [CI], 1.3-1.9; P <.00001), surgery involving the thyroid gland (OR = 8.3; 95% CI, 5.7-12.0; P <.00001), or other neck surgery (OR = 1.7; 95% CI, 1.16-2.42; P = .006) were associated with a higher risk of HT. Caucasians were at higher risk of HT than African Americans (OR = 4.8; 95% CI, 2.8-8.5; P <.00001). The data showed association between lymphangiography and HT but with evidence of publication bias. There was a radiation dose-response relation with a 50% risk of HT at a dose of 45 Gy but with considerable variation in the dose response between studies. Chemotherapy and age were not associated with risk of HT in this analysis. CONCLUSIONS: Several clinical risk factors for HT were identified. The risk of HT increases with increasing radiation dose, but the specific radiation dose response varies between the studies. The most likely cause of this heterogeneity is differences in follow-up between studies.