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Background Deep learning (DL) methods can improve accelerated MRI but require validation against an independent reference standard to ensure robustness and accuracy. Purpose To validate the diagnostic performance of twofold-simultaneous-multislice (SMSx2) twofold-parallel-imaging (PIx2)-accelerated DL superresolution MRI in the knee against conventional SMSx2-PIx2-accelerated MRI using arthroscopy as the reference standard. Materials and Methods Adults with painful knee conditions were prospectively enrolled from December 2021 to October 2022. Participants underwent fourfold SMSx2-PIx2-accelerated standard-of-care and investigational DL superresolution MRI at 3 T. Seven radiologists independently evaluated the MRI examinations for overall image quality (using Likert scale scores: 1, very bad, to 5, very good) and the presence or absence of meniscus and ligament tears. Articular cartilage was categorized as intact, or partial or full-thickness defects. Statistical analyses included interreader agreements (Cohen κ and Gwet AC2) and diagnostic performance testing used area under the receiver operating characteristic curve (AUC) values. Results A total of 116 adults (mean age, 45 years ± 15 [SD]; 74 men) who underwent arthroscopic surgery within 38 days ± 22 were evaluated. Overall image quality was better for DL superresolution MRI (median Likert score, 5; range, 3-5) than conventional MRI (median Likert score, 4; range, 3-5) ( P < .001). Diagnostic performances of conventional versus DL superresolution MRI were similar for medial meniscus tears (AUC, 0.94 [95% CI: 0.89, 0.97] vs 0.94 [95% CI: 0.90, 0.98], respectively; P > .99), lateral meniscus tears (AUC, 0.85 [95% CI: 0.78, 0.91] vs 0.87 [95% CI: 0.81, 0.94], respectively; P = .96), and anterior cruciate ligament tears (AUC, 0.98 [95% CI: 0.93, >0.99] vs 0.98 [95% CI: 0.93, >0.99], respectively; P > .99). DL superresolution MRI (AUC, 0.78; 95% CI: 0.75, 0.81) had higher diagnostic performance than conventional MRI (AUC, 0.71; 95% CI: 0.67, 0.74; P = .002) for articular cartilage lesions. DL superresolution MRI did not introduce hallucinations or erroneously omit abnormalities. Conclusion Compared with conventional SMSx2-PIx2-accelerated MRI, fourfold SMSx2-PIx2-accelerated DL superresolution MRI in the knee provided better image quality, similar performance for detecting meniscus and ligament tears, and improved performance for depicting articular cartilage lesions. © RSNA, 2025 Supplemental material is available for this article. See also the editorial by Nevalainen in this issue.