Purpose To examine if shear-wave elastography (SWE) improves the accuracy of diagnosing soft-tissue masses as benign or malignant compared with US alone or in combination with MRI. Materials and Methods Two hundred six consecutive adult participants (mean age, 57.7 years; range, 18-91 years), including 89 men (median age, 56.0 years; range, 21-91 years) and 117 women (median age, 59.1 years; range, 18-88 years), who were referred for biopsy of a soft-tissue mass were prospectively recruited from December 2015 through March 2017. Participants underwent B-mode US, MRI, and SWE prior to biopsy. Three musculoskeletal radiologists independently reviewed US images alone, followed by US and MRI images together, and classified lesions as benign, probably benign, probably malignant, or malignant. For SWE, the area under the receiver operating characteristic (ROC) curve (AUC) was calculated for transverse shear-wave velocity (SWV). Multivariable logistic regression was used to investigate the association between SWE and malignancy alongside individual demographic and imaging variables. Results At histologic examination, 79 of 206 (38%) participants had malignant lesions. SWV showed good diagnostic accuracy for lesions classified as benign or probably benign by US alone (AUC = 0.87 [95% confidence interval {CI}: 0.79, 0.95]). SWV did not provide substantive diagnostic information for lesions classified as probably malignant or malignant, whether the classification was made with or without MRI. However, multivariable modeling indicated that diagnostic accuracy may vary by lesion position (interaction P = .02; superficial, odds ratio [OR] = 17.7 [95% CI: 1.50, 207], P = .02; deep/mixed, OR = 0.24 [95% CI: 0.07, 0.86], P = .03) and participant age (interaction P = .01; eg, age 43 years, OR = 0.72 [95% CI: 0.15, 3.5], P = .69; age 72 years, OR = 0.08 [95% CI: 0.02, 0.37], P = .001). Conclusion Shear-wave elastography can increase accuracy of soft-tissue lesion diagnosis in conjunction with US. However, a single cut-off may not be universally applicable with diagnostic accuracy that is affected by lesion position and patient age. © RSNA, 2018 Online supplemental material is available for this article.