Limited data exist regarding outcomes for patients on home oxygen undergoing open-heart surgery. This study explores these outcomes with the aim of helping guide future decision-making and expectations. A single-center, retrospective analysis of patients on home oxygen who underwent open-heart surgery between 2014 and 2023 was performed. Patients were divided into two groups and compared based on procedure type: Isolated coronary artery bypass grafting (CABG), or any other open-heart surgery with or without a concurrent CABG procedure (non-isolated CABG/NI-CABG). Primary outcomes included operative mortality and 60-day mortality. The final cohort included 47 patients, 15 in the CABG group and 32 in the NI-CABG group. Despite NI-CABG patients having higher Society of Thoracic Surgeons (STS) scores than CABG patients, there was no significant difference in operative or 60-day mortality between the two groups. The ratio of observed-to-expected mortality was 4.17 in CABG patients and 0.78 in NI-CABG patients. Patients undergoing cardiac surgery on home oxygen therapy have an increased risk of mortality. Our data suggest, however, that the mortality risk may be underestimated for isolated CABG patients and overestimated for patients undergoing other open-heart procedures. Heightened scrutiny should be used when evaluating home oxygen patients for isolated CABG.