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Background: Guideline-directed medical therapy (GDMT) optimization can improve outcomes in heart failure with reduced ejection fraction., Objectives: The objective of this study was to determine if a novel computable algorithm appropriately recommended GDMT., Methods: Clinical trial data from the GUIDE-IT (Guiding Evidence-Based Therapy Using Biomarker Intensified Treatment in Heart Failure) and HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trials were evaluated with a computable medication optimization algorithm that outputs GDMT recommendations and a medication optimization score (MOS). Algorithm-based recommendations were compared to medication changes. A Cox proportional-hazards model was used to estimate the associations between MOS and the composite primary end point for both trials., Results: The algorithm recommended initiation of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blockers, and mineralocorticoid receptor antagonists in 52.8%, 34.9%, and 68.1% of GUIDE-IT visits, respectively, when not prescribed the drug. Initiation only occurred in 20.8%, 56.9%, and 15.8% of subsequent visits. The algorithm also identified dose titration in 48.8% of visits for angiotensin-converting enzyme inhibitor/angiotensin receptor blockers and 39.4% of visits for beta-blockers. Those increases only occurred in 24.3% and 36.8% of subsequent visits. A higher baseline MOS was associated with a lower risk of cardiovascular death or heart failure hospitalization (HR: 0.41; 95% CI: 0.21-0.80; P  = 0.009) in GUIDE-IT and all-cause death and hospitalization (HR: 0.61; 95% CI: 0.44-0.84; P  = 0.003) in HF-ACTION., Conclusions: The algorithm accurately identified patients for GDMT optimization. Even in a clinical trial with robust protocols, GDMT could have been further optimized in a meaningful number of visits. The algorithm-generated MOS was associated with a lower risk of clinical outcomes. Implementation into clinical care may identify and address suboptimal GDMT in patients with heart failure with reduced ejection fraction., Competing Interests: Dr Dorsch is supported by R18 HS026874 from the Agency for Health Research and Quality, R01 AG062582 and R61 HL155498 from the 10.13039/100000002National Institutes of Health, and the American Health Association Health IT Strategically Focused Research Network. Dr Hummel is supported by a grant from 10.13039/100000738Veterans Affairs CARA-009-16F9050 and R01 AG062582 and R61 HL155498 from the 10.13039/100000002National Institutes of Health. Dr Koelling is supported by R01 AG062582 from the 10.13039/100000002National Institutes of Health. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)