Background There is variable evidence and no randomized trials on the benefit of US elastography-guided fine-needle aspiration cytology (FNAC) over conventional US-guided FNAC alone for thyroid nodules. Purpose To compare the efficacy of US elastography-guided FNAC versus US-guided FNAC in reducing nondiagnostic rates for thyroid nodules. Materials and Methods A pragmatic, multicenter randomized controlled trial was performed at 18 secondary and tertiary hospitals across England between February 2015 and September 2018. Eligible adults with single or multiple thyroid nodules who had not previously undergone FNAC were randomized (1:1 ratio) to US elastography FNAC (intervention) or conventional US FNAC (control). The primary outcome was the proportion of patients who have a nondiagnostic cytologic Thy1 (British Thyroid Association system) result following the first FNAC. Results A total of 982 participants (mean age, 51.3 years ± 15 [SD] [IQR, 39-63]; male-to-female ratio, 1:4) were randomized. Of the 493 participants who underwent US elastography, 467 (94.7%) were examined with strain US elastography. There was no difference between the two arms in the nondiagnostic (Thy1) rate following the first FNAC (19% vs 16%; risk difference [RD], 0.03 [95% CI: -0.01, 0.07]; P = .11) or in the median time to reach the final definitive diagnosis (3.3 months [IQR, 1.5-6.4] for US elastography FNAC vs 3.4 months [IQR, 1.5-6.2] for US FNAC). All sensitivity analyses supported the primary analysis. Fewer participants in the US elastography FNAC arm underwent diagnostic hemithyroidectomy than in the US FNAC arm (183 of 493 [37%] vs 196 of 489 [40%]), but this was not statistically significant (adjusted RD, 0.02 [95% CI: -0.06, 0.01]; P = 0.15). There was no evidence of a difference in malignancy rates between the two arms: 70 of 493 (14%) in US elastography FNAC arm versus 79 of 489 (16%) in US FNAC arm (P = .39). There was also no difference in the rate of benign histologic findings between the groups (RD, -0.01 [95% CI: -0.04, 0.03]; P = .7). Conclusion Strain US elastography does not appear to have additional benefit over conventional US FNAC in the diagnosis of malignancy in thyroid nodules. Clinical trial registration no. ISRCTN18261857 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Isikbay and Harwin in this issue.