The purpose of this study was to determine the diagnostic test characteristics of serum neuregulin-1β (NRG-1β) for the detection of acute coronary syndrome (ACS). We recruited emergency department patients presenting with signs and symptoms prompting an evaluation for ACS. Serum troponin and neuregulin-1β levels were compared between those who had a final discharge diagnosis of myocardial infarction (STEMI and NSTEMI) and those who did not, as well as those who more broadly had a final discharge diagnosis of ACS (STEMI, NSTEMI, and unstable angina). Of 319 study participants, 11% had evidence of myocardial infarction, and 19.7% had a final diagnosis of ACS. Patients with MI had median neuregulin levels of 0.16 ng/mL (IQR [0.16-24.54]). Compared to the median of those without MI, 1.46 ng/mL (IQR [0.16-15.02]), there was no significant difference in the distribution of results (P = 0.63). Median neuregulin levels for patients with ACS were 0.65 ng/mL (IQR [0.16-24.54]). There was no statistical significance compared to those without ACS who had a median of 1.40 ng/mL (IQR [0.16-14.19]) (P = 0.95). Neuregulin did not perform successfully as a biomarker for acute MI or ACS in the emergency department.