Foundational guideline-directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction (HFrEF) now consists of 4 classes. There is limited real-world evidence for outcomes associated with GDMT or GDMT with cardiac implantable electronic device therapies (here, implantable cardiac defibrillators [ICDs]/cardiac resynchronization therapy defibrillators [CRT-Ds]). The present study assessed outcomes associated with GDMT or GDMT with ICD/CRT-D for patients with HFrEF and left ventricular ejection fraction (LVEF) ≤35%. We analyzed patients (age ≥18 years) with HFrEF (LVEF ≤35%) in a deidentified real-world dataset including 5,218,134 patients from 20 US institutions with appropriate permissions (egnite Database; egnite, Aliso Viejo, CA, US). Treatment rates, LVEF improvement, and all-cause mortality were examined using unadjusted Kaplan–Meier analysis with first documented echocardiogram with LVEF ≤35% as index event. Mortality analysis used prescribed GDMT class count and device placement as time-varying covariates and censored patients at last clinical encounter. Treatment rate and LVEF improvement analysis censored patients at last clinical encounter/death. Of 362,693 patients with documented HF, 22,061 were included with LVEF ≤35%, prescription history through ≥1 year pre-index, and no device therapy pre-index. Median (IQR) time from index to censor/death was 13.5 (4.2–27.1) months. At index, 95.7%, 73.5%, 29.4%, and 3.5% of patients had ≥1, 2, 3, or all 4 GDMT classes prescribed, respectively. At 18 months, an estimated (95% CI) 98.7% (98.5–98.9%), 84.8% (84.5–85.1%), 43.2% (42.7–43.7%), and 8.1% (7.7–8.4%) had ≥1, 2, 3, or all 4 GDMT classes prescribed, respectively; an estimated 15.3% (14.7–15.9%) had device placement. Of those without a device, by 18 months, an estimated 39.1% (38.2–40.0%) had a documented LVEF >35%. Cohorts with a device and 2, 3, or 4 GDMT classes prescribed had estimated 18-month survival of 83.1% (79.2–87.2%), 85.4% (82.0–89.0%), or 88.9% (83.5–94.8%), respectively (Figure). There were insufficient data for analysis of those with a device and 0/1 GDMT classes. Cohorts without a device and 0, 1, 2, 3, or 4 GDMT classes prescribed had estimated 18-month survival of 70.8% (66.3–75.6%), 73.4% (71.7–75.2%), 77.8% (76.8–78.8%), 81.8% (80.7–82.9%), and 87.6% (85.4–89.9%), respectively (Figure). Higher counts of GDMT classes prescribed and device therapy with GDMT were associated with greater survival in this population.