In Brief Objective To assess the accuracy of sonographic prediction of clinically significant twin birth weight discordance (25% or greater) and to determine whether this accuracy is affected by defined fetal and maternal variables. Methods Using an established database, we reviewed 338 twin gestations delivered over 10 years as a retrospective cohort. Estimation of fetal weight was calculated by applying the Hadlock formula using composite fetal biometry. Intertwin weight discordance was calculated as the difference in the estimated or actual twin weights (A–B) divided by the weight of the larger twin and was expressed as a percentage. Statistical evaluation included validity (sensitivity, specificity, and predictive values) and reliability assessment of ultrasonographic measurements (intraclass correlation coefficients). Multivariable analysis was performed. Results Of 338 twin gestations, 192 (57%) twin pairs met inclusion criteria. Sonographic prediction of actual intertwin birth weight discordance of 25% or greater had a sensitivity of 55%, specificity of 97%, positive predictive value of 82%, and negative predictive value of 91%. The reliability of estimating intertwin birth weight discordance by ultrasonography was moderately high (intraclass correlation coefficient = .700; 95% confidence interval [CI] .620, .765). Multivariable analysis revealed no significant effects of individual maternal or fetal factors on the accuracy of ultrasonographic prediction of intertwin birth weight discordance. Conclusion Sonographic prediction of actual intertwin birth weight discordance of 25% or greater within 16 days of delivery appears to be a valid and reliable method for clinical use. Predictive accuracy is independent of other identifiable maternal or fetal variables. Sonographic prediction of intertwin birth weight discordance of 25% or greater within 16 days of delivery appears to be a valid and reliable method for clinical use.