<h3>Introduction</h3> Limited data exist regarding "real world" use of OTC medications and nutraceuticals in HFrEF patients. <h3>Methods</h3> The EPIC-HF trial (NCT03334188) was a prospective, randomized study testing the implementation, effectiveness, and safety of the EPIC-HF intervention compared to usual care in HFrEF patients across a large diverse health system. Demographic data and nonprescription medication use were collected from electronic medical records. We characterized specific OTC medications and nutraceuticals used by HFrEF patients; assessed attitudes regarding knowledge, skill, and confidence for managing health and healthcare; and compared intensification of guideline directed medical therapy (GDMT) between patients who did or did not use nutraceuticals. Attitudes were assessed via the Patient Activation Measurement tool and stratified by nutraceutical use. The association between guideline-directed medical therapy (GDMT) intensification and nutraceutical use was compared between the EPIC-HF control and intervention groups. Comparisons between groups were made using Mann-Whitney-Wilcoxon tests for continuous variables and chi-squared tests or Fisher's exact test as appropriate for categorical variables. <h3>Results</h3> Of the 305 patients enrolled in the EPIC-HF trial, 92% were taking at least one OTC medication and 26% at least one nutraceutical. The most common OTC medications were aspirin, acetaminophen, cholecalciferol, and calcium. Fish oil, coenzyme Q10, melatonin, and lactobacillus were most used for nutraceuticals. Of the EPIC-HF study cohort, 9.5% of patients were taking an OTC medication or nutraceutical that could exacerbate or worsen HF. In the EPIC-HF intervention cohort (n=147), only 36.4% in the nutraceutical group had any intensification in their GDMT compared to 53.9% of those not taking nutraceuticals (P=0.05). Patients taking nutraceuticals "strongly agreed" they felt more confident when they needed medical care or could handle a health problem themselves compared to those who did not (52.6% vs 39.3%, p<0.05, respectively). <h3>Conclusions</h3> Within our study population, OTC medication use was highly prevalent in patients with HFrEF with about one-third taking nutraceuticals some of which could exacerbate or worsen heart failure. Nutraceutical use among HFrEF patients was associated with a lower likelihood for GDMT intensification.