Background: Mammographic density measurements are used to identify patients who should undergo supplemental imaging for breast cancer detection, but artificial intelligence (AI) image analysis may be more effective.<br /> Purpose: To assess whether AISmartDensity-an AI -based score integrating cancer signs, masking, and risk-surpasses measurements of mammographic density in identifying patients for supplemental breast imaging after a negative screening mammogram. Materials and Methods: This retrospective study included randomly selected individuals who underwent screening mammography at Karolinska University Hospital between January 2008 and December 2015. The models in AISmartDensity were trained and validated using nonoverlapping data. The ability of AISmartDensity to identify future cancer in patients with a negative screening mammogram was evaluated and compared with that of mammographic density models. Sensitivity and positive predictive value (PPV) were calculated for the top 8% of scores, mimicking the proportion of patients in the Breast Imaging Reporting and Data System "extremely dense" category. Model performance was evaluated using area under the receiver operating characteristic curve (AUC) and was compared using the DeLong test.<br /> Results: The study population included 65 325 examinations (median patient age, 53 years [IQR, 47-62 years])-64 870 examinations in healthy patients and 455 examinations in patients with breast cancer diagnosed within 3 years of a negative screening mammogram. The AUC for detecting subsequent cancers was 0.72 and 0.61 ( P < .001) for AISmartDensity and the best -performing density model (age -adjusted dense area), respectively. For examinations with scores in the top 8%, AISmartDensity identified 152 of 455 (33%) future cancers with a PPV of 2.91%, whereas the best -performing density model (age -adjusted dense area) identified 57 of 455 (13%) future cancers with a PPV of 1.09% ( P < .001). AISmartDensity identified 32% (41 of 130) and 34% (111 of 325) of interval and next -round screen -detected cancers, whereas the best -performing density model (dense area) identified 16% (21 of 130) and 9% (30 of 325), respectively.<br /> Conclusion: AISmartDensity, integrating cancer signs, masking, and risk, outperformed traditional density models in identifying patients for supplemental imaging after a negative screening mammogram.