Purpose To determine the relationship between target lesion selection with use of Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and classification of therapeutic response in patients with metastatic cancer undergoing systemic cytotoxic and/or targeted therapies. Materials and Methods This prospective multireader study was conducted between July 2015 and July 2017. Three hundred sixteen consecutive participants with metastatic cancer underwent 932 CT examinations to monitor systemic treatment. CT studies were independently read by three radiologists. Readers identified a maximum of five lesions total (and a maximum of two lesions per organ). Dedicated oncology tumor response software was used. The Fleiss κ statistic was used to analyze interreader agreement in the assignment of individual response classes (complete response, partial response, progressive disease, or stable disease) and in the differentiation between progressive and nonprogressive disease. Results Readers selected the same set of target lesions in 128 of the 316 participants (41%) and selected a different set in 188 (59%). When target lesion selection was concordant, agreement was high (assignment of treatment response category: κ = 0.97; 95% confidence interval [CI]: 0.91, 1.0; differentiation between progressive and nonprogressive disease: κ = 0.98; 95% CI: 0.90, 1.0). When target lesion selection was discordant, agreement was significantly reduced (assignment of treatment response category: κ = 0.58; 95% CI: 0.54, 0.62; differentiation between progressive and nonprogressive disease: κ = 0.6; 95% CI: 0.59, 0.70). With concordant target lesion selection, readers agreed regarding diagnosis of progression in 97.7% of participants (95% CI: 95.4%, 100.0%); with discordant target lesion selection, readers agreed in only 55.3% (95% CI: 47.9%, 62.6%) (P < .01). Conclusion In patients with metastatic cancer undergoing systemic treatment, different cancer sites may appear similarly suitable and thus likely to be selected as target lesions but may yield inconsistent or even conflicting results with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. This indicates that the current, limited set of target lesions in RECIST 1.1 may not reflect overall tumor load or response to therapy. © RSNA, 2018 See also the editorial by Sosna in this issue.