Background Accurate breast cancer risk assessment after a negative screening result could enable better strategies for early detection. Purpose To evaluate a deep learning algorithm for risk assessment based on digital mammograms. Materials and Methods A retrospective observational matched case-control study was designed using the OPTIMAM Mammography Image Database from the National Health Service Breast Screening Programme in the United Kingdom from February 2010 to September 2019. Patients with breast cancer (cases) were diagnosed following a mammographic screening or between two triannual screening rounds. Controls were matched based on mammography device, screening site, and age. The artificial intelligence (AI) model only used mammograms at screening before diagnosis. The primary objective was to assess model performance, with a secondary objective to assess heterogeneity and calibration slope. The area under the receiver operating characteristic curve (AUC) was estimated for 3-year risk. Heterogeneity according to cancer subtype was assessed using a likelihood ratio interaction test. Statistical significance was set at P < .05. Results Analysis included patients with screen-detected (median age, 60 years [IQR, 55-65 years]; 2044 female, including 1528 with invasive cancer and 503 with ductal carcinoma in situ [DCIS]) or interval (median age, 59 years [IQR, 53-65 years]; 696 female, including 636 with invasive cancer and 54 with DCIS) breast cancer and 1:1 matched controls, each with a complete set of mammograms at the screening preceding diagnosis. The AI model had an overall AUC of 0.68 (95% CI: 0.66, 0.70), with no evidence of a significant difference between interval and screen-detected (AUC, 0.69 vs 0.67; P = .085) cancer. The calibration slope was 1.13 (95% CI: 1.01, 1.26). There was similar performance for the detection of invasive cancer versus DCIS (AUC, 0.68 vs 0.66; P = .057). The model had higher performance for advanced cancer risk (AUC, 0.72 ≥stage II vs 0.66 <stage II; P = .037). The AUC for detecting breast cancer in mammograms at diagnosis was 0.89 (95% CI: 0.88, 0.91). Conclusion The AI model was found to be a strong predictor of breast cancer risk for 3-6 years following a negative mammographic screening. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Mann and Sechopoulos in this issue.