<h3>Purpose/Objective(s)</h3> Primary hypothyroidism is a common late complication in patients who underwent head and neck radiotherapy, occurring at incidences as high as 20-50% among long-term survivors. Various radiation dose-volume constraints for the thyroid gland have been proposed in retrospective series, but none has been externally validated for predicting long-term thyroid function outcome. <h3>Materials/Methods</h3> We undertook a systematic review of the literature and identified 22 distinct radiation dose-volume constraints of the thyroid gland for head and neck radiotherapy planning. We reviewed the thyroid gland dosimetry of 488 consecutive head and neck cancer patients who had normal baseline thyroid function and underwent definitive radiotherapy between January 2013 and December 2015 in two tertiary oncology centers. Thyroid function was monitored at least yearly after radiotherapy. Primary hypothyroidism was defined as serum TSH levels above the upper limit of normal. Time to hypothyroidism was estimated using cumulative incidence function with death designated as a competing event. Univariable and multivariable analyses were conducted using Gray's test the Fine-Gray sub-distribution hazard model. Diagnostic performances of the 22 constraints were compared using time-dependent receiver operating characteristic curves. <h3>Results</h3> With a median follow-up of 6.8 years, 205 (42.0%) patients developed post-radiation primary hypothyroidism. The 5-year primary hypothyroidism rate was 30.5%. Among all candidate dose-volume parameters (Dmin, Dmax, Dmean, V25, V30, V30, V35, V40, V45, V50, V30-60, VS45 and VS60), thyroid volume spared from 60Gy (VS60) had the largest areas under curve of 0.715, 0.694 and 0.698, at 1 year, 3 years and 5 years after radiotherapy, respectively. The sensitivity, specificity, positive predictive value and negative predictive value for VS60 ≥10cc on 5-year hypothyroidism risk were 84.4%, 40.3%, 38.5% and 85.4%, respectively. Among all evaluated constraints, VS60 ≥10cc had the highest F-score of 0.59, suggesting a superior overall diagnostic accuracy. The 5-year hypothyroidism risk for patients with thyroid VS60 ≥10cc and VS60 <10cc were 14.7% and 38.2%, respectively (p <0.001). In multivariate regression, young age, VS60 <10cc and small thyroid volume and were independent predictors for post-radiation primary hypothyroidism. The adjusted sub-hazard ratio for post-radiation primary hypothyroidism for VS60 <10cc was 2.00 (95% C.I., 1.33 – 3.07; p <0.001). <h3>Conclusion</h3> Our external validation study identified thyroid VS60 as the best radiation dose-volume parameter to predict long-term thyroid gland function in patients who underwent head and neck radiotherapy. VS60 >10cc is a potentially useful constraint that limits 5-year primary hypothyroidism risk to below 15%. As far as it is feasible during radiotherapy optimization, higher VS60 targets should be considered to further reduce the risk of this late complication among head and neck cancer patients.