ObjectivesTo explore the association between intraoperative methadone use, postoperative pain, and opioid consumption after coronary artery bypass grafting (CABG) surgery. DesignRetrospective cohort study. SettingSingle academic medical center. ParticipantsPatients having isolated CABG over a five-year period. InterventionsNone Measurements and Main ResultsDemographics, comorbidities, and intraoperative anesthetic medications were recorded. Primary study outcomes were average and maximum pain scores and morphine milligram equivalent (MME) consumption after surgery for the first two postoperative days (PODs). Linear mixed effects regression models were used to examine the effect of intraoperative methadone use on study outcomes. Among 1,338 patients, 78.6% received intraoperative methadone (0.2 mg/kg). Patients who did not receive methadone had higher average (Est = 0.48, 95% CI= 0.22, 0.73, p<.001) and maximum postoperative (Est = 0.49, 95% CI=0.23, 0.75, p<.001) pain scores over POD 0 to 2. For postoperative opioid consumption, there was a significant intraoperative methadone use x time interaction effect on postoperative opioid use (OR = 2.21, 95% CI = 1.74, 2.80, p<.001). Across PODs 0 to 2, patients who received intraoperative methadone had a faster decline in postoperative opioid use compared to those who did not receive intraoperative methadone. Patients who did not receive intraoperative methadone were extubated slightly faster (OR = 0.82, 95% CI = 0.72, 0.93, p<.01). ConclusionsOur data suggest that the use of intraoperative methadone is safe, reduces postoperative pain, and expedites weaning from postoperative opioids after CABG surgery.